Polymer release system

ABSTRACT

A method for controlling the release of at least one therapeutically, prophylactically and/or diagnostically active substance into an aqueous medium by erosion of at least one surface of a pharmaceutical composition. The method comprises adjusting the concentration and/or the nature of the ingredients making up the matrix composition in such a manner so as to obtain an approximately zero order release of the active substance from the pharmaceutical composition when subject to an in vitro dissolution test as described herein. The composition comprises i) a matrix composition comprising a) a polymer or a mixture of polymers that may be substantially water soluble and/or crystalline, b) an active substance and, optionally, c) one or more pharmaceutically acceptable excipients, and ii) a coating. Typical polymers are PEO. The coating comprises a first cellulose derivative which is substantially insoluble in the aqueous medium, and at least one of a) a second cellulose derivative which is soluble or dispersible in water, b) a plasticizer, and c) a filler. The active ingredient may be carvedilol. Stable solid dispersions of active substances having low water solubility are also disclosed.

FIELD OF THE INVENTION

[0001] The present invention relates to a novel method for controllingthe release of a therapeutically, prophylactically and/or diagnosticallyactive substance from a pharmaceutical composition into an aqueousmedium. The pharmaceutical composition is a coated matrix composition inwhich the matrix composition comprises a) polymer or a mixture ofpolymers, b) an active substance and, optionally, c) one or morepharmaceutically acceptable excipients. In a specific embodiment, thepolymer is a substantially water soluble or crystalline polymer or amixture of substantially water soluble and/or crystalline polymers. Thecoating remains intact during the release phase and may thereaftercrumble and/or erode. Furthermore, the coating covers the matrixcomposition in such a manner that only a specific surface area of thematrix composition is subject to erosion in an aqueous medium, i.e. thesurface area from which the active substance is release is keptsubstantial constant during the time period

[0002] The method is based on the finding that it is possible to controlthe release from such a composition by ensuring that the releasepredominantly takes place by erosion. In order to ensure erosion basedrelease, a balance must be obtained between the diffusion rate of waterinto the matrix composition and the dissolution rate of the matrixcomposition.

[0003] The invention also relates to a pharmaceutical composition, whichprovides zero order release based on controlling the balance betweenmatrix erosion rate and diffusion rate in the matrix.

DETAILED DESCRIPTION OF THE INVENTION

[0004] During the last decades many different systems for modifying therelease of an active drug substance from a pharmaceutical compositionhave been developed. Most of them aim at obtaining a zero or a firstorder release rate of the active substance from the composition. Zeroorder release rate (i.e. constant release of the active substance withtime) seems to be very difficult to obtain from a pharmaceuticalcomposition. The present invention is based on a polymeric matrixcomposition, which is construed to deliver the active substance in azero order release manner. The present invention is a furtherdevelopment based on the Applicant's previously described drug deliverysystems, see e.g. EP-B-0 406 315, EP-B-0 493 513, EP-B-0 740 310 and WO99/51208 the disclosure of which is hereby incorporated by reference.

[0005] In particular, it has surprisingly been found that it is possibleto obtain zero order release from a polymeric matrix composition withoutany content of a water dispersible or water soluble surface active agentor a mixture of such surface active agents which has at least one domainwhich is compatible with the polymer in the polymer matrix compositionand at least one other domain which is substantially lipophilic andwhich has a melting point that is lower than the polymer used in thepolymeric matrix composition. The presence of such a substance (e.g.like PEG 400 monostearate or PEG 2000 monostearate) has beencontemplated to function as a so-called repair medium. Such a repairmedium has a substantially hydrophilic domain, which gives it affinityto the (crystalline) polymeric phase, thereby filling in domains betweengrains and cracks in the polymer matrix and reducing the water affinityof these domains and in the polymer matrix itself. Water diffusion inthe interface between the polymer crystals is thereby substantiallyeliminated, thus substantially limiting diffusion of water into thecomposition to the surface layer of the matrix, so that erosion of thecomposition is predominantly effected by the dissolving action of theaqueous phase on a surface or surfaces of the composition exposed to theaqueous medium. In other words a repair medium seems to prevent thediffusion of water in the polymer matrix composition.

[0006] However, in certain cases, the present inventors have observedthat inclusion of a water soluble surface active agent has a negativeimpact on the mobility and/or stability of a composition.

[0007] However, the present inventors have found that it is possible toobtain a zero order release from a polymer matrix composition althoughwater may be able to diffuse into the matrix. When water diffuse intothe polymer matrix composition a resulting boundary layer (or swellinglayer) can be formed at the surface of the matrix composition, which isexposed to the aqueous medium. In general the diffusion of an activesubstance through such a boundary layer is important for the release ofan active substance and, accordingly, the thickness of the boundarylayer is important for the release rate. However, the present inventorshave found that it is possible to eliminate or substantially eliminatethe impact of the boundary layer on the release rate of the activesubstance from a polymer matrix composition by ensuring that thethickness of the boundary layer is relatively small and/or that therelease of the active substance from a polymer matrix composition isgoverned by erosion of the composition and the diffusion of the activesubstance through the boundary layer, if any, has no or only a smallimpact on the overall release rate.

[0008] The present inventors have found that when water is allowed todiffuse into a polymer matrix composition zero order release is obtainedwhen the release rate is governed or controlled by erosion of a constantsurface area per time unit. In order to ensure that the erosion of thepolymer matrix composition is the predominant release mechanism, theinventors have found that it is necessary to provide a polymer matrixcomposition which has properties that ensures that the diffusion rate ofwater into the polymer matrix composition substantially corresponds tothe dissolution rate of the polymer matrix composition into the aqueousmedium. Thus, by adjusting the nature and amount of constituentscontained in the polymer matrix composition along this line the presentinventors have obtained polymer matrix compositions, which release theactive substance by a zero order release mechanism. The compositionsemployed are coated in such a manner that at least one surface isexposed to the aqueous medium and this surface has a substantiallyconstant or controlled surface area during erosion. In the presentcontext controlled surface area relates to a predetermined surface areatypically predicted from the shape of the coat of the unit dosagesystem. It may have a simple uniform cylindrical shape or thecylindrical form can have one or more tapered ends in order to decrease(or increase) the initial release period.

[0009] Accordingly, the present invention provides a method forcontrolling the release of at least one therapeutically,prophylactically and/or diagnostically active substance into an aqueousmedium by erosion of at least one surface of a pharmaceuticalcomposition comprising

[0010] i) a matrix composition comprising a) a polymer or a mixture ofpolymers, b) an active substance and, optionally, c) one or morepharmaceutically acceptable excipients, and

[0011] ii) a coating having at least one opening exposing at the onesurface of said matrix, the coating comprising

[0012] a) a first cellulose derivative which has thermoplasticproperties and which is substantially insoluble in the aqueous medium inwhich the composition is to be used, and at least one of

[0013] b) a second cellulose derivative which is soluble or dispersiblein water,

[0014] c) a plasticizer, and

[0015] d) a filler,

[0016] the method comprising adjusting the concentration and/or thenature of the ingredients making up the matrix composition in such amanner that the diffusion rate of the aqueous medium into the matrixcomposition corresponds to about 100%±30% such as, e.g. about 100%±25%,about 100%±20%, about 100%±15% or about 100%±10% or about 100% of thedissolution rate of the matrix composition so as to obtain a zero orderrelease of at least about 60% w/w such as, e.g. at least about 65% w/wat least about 70% w/w, at least about 75% w/w, at least about 80% w/w,at least about 85% w/w, at least about 90% w/w, at least about 95% w/wor at least about 97 or 98% w/w of the active substance from thepharmaceutical composition when subject to an in vitro dissolution testas described herein.

[0017] In a specific embodiment, the polymer is a substantially watersoluble or crystalline polymer or a mixture of substantially watersoluble and/or crystalline polymers

[0018] By use of such a method it is possible already during thedevelopmental work to test various polymer matrix compositions withrespect to diffusion rate of water into the composition and todissolution rate of the polymer matrix composition in an aqueous medium.Based on such results adjustment of e.g. the concentration and/or natureof the individual constituents in the composition may be performed untilthe diffusion rate balance the dissolution rate. In such a manner, arelatively simple instrument has been provided in order to ensure a zeroorder-release rate from the final composition.

[0019] In another aspect, the invention relates to a pharmaceuticalcomposition for controlled release of at least one therapeutically,prophylactically and/or diagnostically active substance into an aqueousmedium by erosion of at least one surface of the composition, thecomposition comprising

[0020] i) a matrix composition comprising a) a polymer or a mixture ofpolymers, b) an active substance and, optionally, c) one or morepharmaceutically acceptable excipients, and

[0021] ii) a coating having at least one opening exposing at the onesurface of said matrix, the coating comprising

[0022] a) a first cellulose derivative which has thermoplasticproperties and which is substantially insoluble in the aqueous medium inwhich the composition is to be used,

[0023] and at least one of

[0024] b) a second cellulose derivative which is soluble or dispersiblein water,

[0025] c) a plasticizer, and

[0026] d) a filler,

[0027] and the concentration and/or the nature of the ingredients makingup the matrix composition has been adjusted in such a manner that thediffusion rate of the aqueous medium into the matrix compositioncorresponds to about 100%±30% such as, e.g. about 100%±25%, about100%±20%, about 100%±15% or about 100%±10% or about 100% of thedissolution rate of the matrix composition so as to obtain a zero orderrelease of at least about 60% w/w such as, e.g. at least about 65% w/wat least about 70% w/w, at least about 75% w/w, at least about 80% w/w,at least about 85% w/w, at least about 90% w/w, at least about 95% w/wor at least about 97 or 98% w/w of the active substance from thepharmaceutical composition when subject to an in vitro dissolution testas described herein.

[0028] In a specific embodiment, the polymer is a substantially watersoluble or crystalline polymer or a mixture of substantially watersoluble and/or crystalline polymers

Matrix Composition

[0029] The pharmaceutical composition according to the inventioncomprises a matrix composition comprising

[0030] a) a polymer or a mixture of polymers,

[0031] b) an active substance and, optionally,

[0032] c) one or more pharmaceutically acceptable excipients.

[0033] In a specific embodiment, the polymer is a substantially watersoluble or crystalline polymer or a mixture of substantially watersoluble and/or crystalline polymers

[0034] Polymers

[0035] The substantially water soluble or crystalline polymer or amixture of substantially water soluble and/or crystalline polymers (inthe following denoted: “the polymer”) typically comprises a polyglycol,e.g. in the form of a homopolymer and/or a copolymer. Suitable polymersfor use in a composition according to the invention are polyethyleneoxides and/or block copolymers of ethylene oxide and propylene oxide.Polyethylene oxides which are suitable for use in the matrix compositionare those having a molecular weight of from about 20,000 daltons, suchas, e.g., from about 20,000 to about 700,000 daltons, from about 20,000to about 600,000 daltons, from about 35,000 to about 500,000 daltons,from about 35,000 to about 400,000 daltons, from about 35,000 to about300,000 daltons, from about 50,000 to about 300,000 daltons, such as,e.g. about 35,000 daltons, about 50,000 daltons, about 75,000 daltons,about 100,000 daltons, about 150,000 daltons, about 200,000 daltons,about 250,000 daltons, about 300,000 daltons or about 400,000 daltons.

[0036] A particular suitable polyethylene oxide is one, which in itselfhas a suitable balance between the diffusion rate of water into thepolymer and a dissolution rate of the polymer. Suitable examples arepolyethylene oxides having a molecular weight of about 35,000 daltons,about 50,000 daltons, about 100,000 daltons, about 200,000 daltons,about 300,000 daltons and about 400,000.

[0037] Typical block copolymers of ethylene oxide and propylene oxidemay comprise up to about 30% w/w of the propylene oxide based block, andhas a molecular weight of about 5,000 daltons, typically about 5,000 toabout 30,000 daltons such as, e.g. from about 8,000 to about 15,000daltons.

[0038] Polyethylene glycols (which when the molecular weight is aboveabout 20,000 is denoted polyethylene oxides) are mixtures ofcondensation polymers of ethylene glycol.

[0039] The average molecular weight (MW) can be calculated from thefollowing equation MW=(56,110×2)/hydroxyl number

[0040] Where the hydroxyl number is defined as the number indicating theamount in mg of potassium hydroxide, which is equivalent to the aceticacid, which, by acetylation, is bound by 1 g of a substance.

[0041] Mixtures of PEO with different average molecular weights can beused in order to obtain a PEO with a desirable average molecular weight.It is important to note that in such cases it is necessary to use thePEO, which have MW closest to the desired molecular weight. Theindividual amount of the two PEO necessary to obtain a PEO with adesired MW can be calculated from the hydroxyl number and the equationgiven above.

[0042] The polymer may have a melting point, which is above the bodytemperature of the human or animal in which the composition is to beused. Thus, the polymer(s) employed in the matrix composition willsuitably have a melting point of about 20-120° C. such as, e.g. fromabout 30 to about 100° C. or from about 40 to about 80° C.

[0043] Altematively to a polymer of a polyglycol type as described aboveother polymers may be suitable for use in the matrix composition a).Thus, in other embodiments of the invention, the polymer is selectedfrom one or more of the following polymers: water soluble naturalpolymers such as glucomannan, galactan, glucan, polygalacturonic acid,polyxylane, polygalactomannans, rhanogalacturonan, polyxyloglycan,arabinogalactan, and starch; water soluble polymers such as PVA, PVB,methocel, Eudragit L methyl ester and PHPV; biodegradable polymers suchas PHA, and PLA; hydrogels, such as olyacrylic amid, and dextran;copolymers such as polylactic acid with polyglycolic acid; and otherssuch as alginate and pectins including low methylated or methoxylatedpectins.

[0044] Active Substances

[0045] A pharmaceutical composition according to the invention comprisesone or more active substances, i.e. substances, which aretherapeutically, prophylactically, diagnostically and/or biologicallyactive substance. The term “active substance” as used herein broadlyincludes any compound, or mixture thereof, that can be delivered fromthe composition to produce a beneficial result. The active andbeneficial agents include pesticides, herbicides, germicides, biocides,algicides, rodenticides, fungicides, insecticides, antioxidants, planthormone promoters, plant growth inhibitors, preservatives,disinfectants, sterilization agents, catalysts, chemical reactants,fermentation agents, food supplements, nutrients, cosmetics,therapeutically active substances (drugs), vitamins, sex sterilants,fertility inhibitors, fertility promoters, air purifiers, microorganismattenuators, ecological agents and other agents that benefit theenvironment in which they are used.

[0046] In the present context the term “drug substance” includes anyphysiologically or pharmacologically active substance that produces alocalized or systemic effect in animals, in particular in mammals,including humans and primates. Other animals include domestic household,sport or farm animals such as sheep, goats, cattle, horses and pigs,laboratory animals such as mice, rats and guinea pigs, fishes, avians,reptiles and zoo animals. The term “therapeutically, prophylacticallyand/or diagnostically active substance” includes the term drug substancewithin its meaning.

[0047] In the present context, the term “ecological agent” denotes anon-therapeutic substance that has a biological effect on plants oranimals in the environment. An ecological agent may be a pesticide, suchas an insecticides or herbicide, a fertilizer a pheromone, a plantgrowth hormone or the like.

[0048] The active substance or substances included in a pharmaceuticalcomposition of the invention may be selected from many therapeuticcategories, in particular from substances which may advantageously beadministered orally, rectally, vaginally, or administered to a bodycavity (e.g. the urinary bladder, kidney pelvis, the gall bladder, theuterus, a central nervous system cavity,infectious/malignant/post-operative cavities, etc.).

[0049] Examples of such substances are hypnotics, sedatives,tranquilizers, anti-convulsants, muscle relaxants, analgesics,anti-inflammatory, anaesthetics, anti-spasmodics, anti-ulcer-agents,anti-parasitics, anti-microbials, anti-fungal, cardiovascular agents,diuretics, cytostatics, anti-neoplastic agents, anti-viral agents,anti-glaucoma agents, anti-depressants, sympathomimetics,hypoglycaemics, diagnostic agents, anti-cough, physic energizers,anti-parkinson agents, local anesthetics, muscle contractants,anti-malarials, hormonal agents, contraceptives, anorexic,anti-arthritic, anti-diabetic, anti-hypertensive, anti-pyretic,anti-cholingergic, bronchodilator, central nervous system, inotropic,vasodilator, vasoconstrictor, decongestant, hematine, iron salts andcomplexes, electrolyte supplement, germicidal, parasympathetolytic,parasympathethomimetic, antiemetic, psychostimulant, vitamin,beta-blockers, H-2 blocker, beta-2 agonist, counterirritants,coagulating modifying agents, stimulants, anti-hormones,drug-antagonists, lipid-regulating agents, uricosurics, cardiacglycosides, ergots and derivatives thereof, expectorants,muscle-relaxants, anti-histamines, purgatives, contrastmaterials,radiopharmaceuticals, imaging agents, anti-allergic agents.

[0050] Examples of specific active substances suitable for use in acomposition of the invention are:

[0051] Carvedilol, morphine, diclofenac, nifedipine, calcitonin,rivastigmine, methylphenidate, fluoroxetine, rosiglitazone, prednison,prednisolone, codeine, ethylmorphine, dextromethorphan, noscapine,pentoxiverine, acetylcysteine, bromhexine, epinephrine, isoprenaline,orciprenaline, ephedrine, fenoterol, rimiterol, ipratropium,cholinetheophyllinate, proxiphylline, bechlomethasone, budesonide,deslanoside, digoxine, digitoxin, disopyramide, proscillaridin,chinidine, procainamide, mexiletin, flecainide, alprenolol,proproanolol, nadolol, pindolol, oxprenolol, labetalol, timolol,atenolol, pentaeritrityltetranitrate, isosorbiddinitrate,isosorbidmononitrate, niphedipin, phenylamine, verapamil, diltiazem,cyclandelar, nicotinylalcholhol, inositolnicotinate, alprostatdil,etilephrine, prenalterol, dobutamine, dopamine, dihydroergotamine,guanetidine, betanidine, methyldopa, reserpine, guanfacine,trimethaphan, hydralazine, dihydralazine, prazosine, diazoxid,captopril, nifedipine, enalapril, nitroprusside, bendroflumethiazide,hydrochlorthiazide, metychlothiazide, polythiazide, chlorthalidon,cinetazon, clopamide, mefruside, metholazone, bumetanide, ethacrynacide,spironolactone, amiloride, chlofibrate, nicotinic acid, nicheritrol,brompheniramine, cinnarizine, dexchlorpheniramine, clemastine,antazoline, cyproheptadine, proethazine, cimetidine, ranitidine,sucralfat, papaverine, moxaverine, atropin, butylscopolamin, emepron,glucopyrron, hyoscyamine, mepensolar, methyiscopolamine,oxiphencyclimine, probanteline, tero dilin, sennaglycosides,sagradaextract, dantron, bisachodyl, sodiumpicosulfat, etulos,diphenolxylate, loperamide, salazosulfapyridine, pyrvin, mebendazol,dimeticon, ferrofumarate, ferrosuccinate, ferritetrasemisodium,cyanochobalamine, folid acid heparin, heparin co-factor, diculmarole,warfarin, streptokinase, urokinase, factor Vil, factor IX, vitamin K,thiopeta, busulfan, chlorambucil, cyclophosphamid, melfalan, carmustin,mercatopurin, thioguanin, azathioprin, cytarabin, vinblastin,vinchristin, vindesin, procarbazine, dacarbazine, lomustin, estramustin,teniposide, etoposide, cisplatin, amsachrin, aminogluthetimid,phosphestrol, medroxiprogresterone, hydroxiprogesterone, megesterol,noretisteron, tamoxiphen, ciclosporin, sulfosomidine, bensylpenicillin,phenoxymethylpenicillin, dicloxacillin, cloxacillin, flucoxacillin,ampicillin, amoxicillin, pivampicillin, bacampicillin, piperacillin,mezlocillin, mecillinam, pivmecillinam, cephalotin, cephalexin,cephradin, cephadroxil, cephaclor, cefuroxim, cefotaxim, ceftazidim,cefoxitin, aztreonam, imipenem, cilastatin, tetracycline, lymecycline,demeclocycline, metacycline, oxitetracycline, doxycycline,chloramphenicol, spiramycin, fusidic acid, lincomycin, clindamycin,spectinomycin, rifampicin, amphotericin B, griseofulvin, nystatin,vancomycin, metronidazole, tinidazole, trimethoprim, norfloxacin,salazosulfapyridin, aminosalyl, isoniazid, etambutol, nitrofurantoin,nalidixic acid, metanamine, chloroquin, hydroxichloroquin, tinidazol,ketokonazol, acyclovir, interferon idoxuridin, retinal, tiamin,dexpantenol, pyridoxin, folic acid, ascorbic acid, tokoferol,phytominadion, phenfluramin, corticotropin, tetracosactid, tyrotropin,somatotoprin, somatrem, vasopressin, lypressin, desmopressin, oxytocin,chloriongonadotropin, cortison, hydrocortisone, fluodrocortison,prednison, prednisolon, fluoximesteron, mesterolon, nandrolon,stanozolol, oximetolon, cyproteron, levotyroxin, liotyronin,propylthiouracil, carbimazol, tiamazol, dihydrotachysterol,alfacalcidol, calcitirol, insulin, tolbutamid, chlorpropamid, tolazamid,glipizid, glibenclamid, phenobarbital, methyprylon, pyrityldion,meprobamat, chlordiazepoxid, diazepam, nitrazepam, oxazepam,dikaliumclorazepat, lorazepam, flunitrazepam, alprazolam, midazolam,hydroxizin, chlometiazol, propionmazine, alimemazine, chlorpromazine,levomepromazine, acetophenazine, fluphenazine, perphenazine,prochlorperazine, trifluoperazine, dixyrazine, thiodirazine, periciazin,chloprothixene, zuclopentizol, flupentizol, thithixen, haloperidol,trimipramin, opipramol, chlomipramin, desipramin, lofepramin,amitriptylin, nortriptylin, protriptylin, maptrotilin, caffeine,cinnarizine, cydizine, dimenhydinate, meclozine, prometazine,thiethylperazine, metodopramide, scopolamine, phenobarbital, phenytoine,ethosuximide, primidone, carbamazepine, chlonazepam, orphenadrine,atropine, bensatropine, biperiden, metixene, procyilidine, levodopa,bromocriptin, amantadine, ambenon, pyridostigmine, synstigmine,disulfiram, morphine, codeine, pentazocine, buprenorphine, pethidine,phenoperidine, phentanyl, methadone, piritramide, dextropropoxyphene,ketobemidone, acetylsalicylic acid, phenazone, phenylbutazone,azapropazone, piroxicam, ergotamine, dihydroergotamine, cyproheptadine,pizitifen, flumedroxon, allopurinol, probenecid, sodiummaurothiomalateauronofin, penicillamine, estradiol, estradiolvalerianate, estriol,ethinylestradiol, dihydrogesteron, lynestrenol, medroxiprogresterone,noretisterone, cydophenile, clomiphene, levonorgestrel, mestranol,ornidazol, tinidazol, ekonazol, chlotrimazol, natamycine, miconazole,sulbentin, methylergotamine, dinoprost, dinoproston, gemeprost,bromocriptine, phenylpropanolamine; sodiumchromoglicate, azetasolamide,dichlophenamide, betacarotene, naloxone, calciumfolinate, in particularclonidine, thephylline, dipyradamol, hydrochlothiazade, scopolamine,indomethacine, furosemide, potassium chloride, morphine, ibuprofen,salbutamol, terbutalin, sulfonylurea, mefformin, insulin, calcitonin,glucagons-like peptide-1, or combinations thereof.

[0052] The active substance can be in various forms, such as unchargedmolecules, molecular complexes, crystalline forms, amorphous form,polymorphous form, solvates, anhydrates, pharmacologically acceptablesalts such as a hydrochloride, hydrobromide, sulfate, laurylate,palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate,tartrate, oleate, and salicylate. For acidic active substance, salts ofmetals, amines amino acids or organic cations, quatemary ammoniums, canbe used. Derivatives of active substances such as esters, ethers andamides which have solubility characteristics suitable for use herein canbe used alone or mixed with other drugs. After release of the derivativefrom the drug delivery system it may be converted by enzymes, hydrolysedby body pH or other metabolic processes to the parent drug or to anotherbiologically active form.

[0053] The active substance may be dissolved and/or dispersed in thepolymer matrix. In those cases, where the active substance is dispersedin the matrix, it is present in any of its crystalline, polymorphous oramorphous forms or mixtures thereof.

[0054] In specific embodiments, the active substance may at leastpartially be present in solid form in the dispersion, i.e. some of theactive substance may be dissolved in the polymer (such as, e.g.,polyethylene oxide)provided that at least a part is still present onsolid form.

[0055] In the pharmaceutical technology (and in the present context),the term “solid dispersion” also embraces semi-solid dispersions. By theterm is understood the finely dispersed distribution of one or moresolids, e.g. an active substance like morphine, in an inert solid orsemi-solid carrier. The active substance may be present in moleculardispersed form, i.e. as a solid solution, in fine crystalline dispersedform, in a glassy amorphous phase or dispersed as a fine amorphouspowder. Eutectic mixtures, i.e. crystalline structures of activesubstances and carriers are also encompassed in the definition of “soliddispersions”. Normally, the mean particle size is used to dassifydispersed system. A colloidal dispersion is when the dispersed phase hasa particle size between about 1 and about 1000 nm and a coarselydispersion has a mean particle size of at least about 1000 nm and amolecular dispersion has a particle size below about 1 nm. Combinationsbetween the various states are very likely and the most dominatingcharacter can be determined by X-ray diffraction spectra or differentialthermoanalysis.

[0056] In specific aspects of the present invention some of the activesubstance may be present in a molecular dispersion such as, e.g., in theform of a solid or semi-solid solution.

[0057] In a specific aspect of the invention, a composition comprises anactive substance that at least partially is present in amorphous formwith a mean particle size of at least about 0.01 μm such as, e.g., fromabout 0.01 μm to about 500 μm, from about 0.05 μm to about 500 μm, fromabout 0.1 μm to about 500 μm, from about 0.5 μm to about 500 μm, about 1μm to about 500 μm, typically from about 0.5 μm to about 300 μm, moretypically from about 1 μm to about 200 μm, especially from about 1 μm toabout 100 μm.

[0058] A pharmaceutical composition of the invention may in addition besuitable for the delivery of polypeptides, for example hormones, enzymessuch as lipases, proteases, carbohydrates, amylases, lactoferrin,lactoperoxidases, lysozymes, nanoparticles, etc., and antibodies. Thecomposition may also be employed for the delivery of microorganisms,either living, attenuated or dead, for example bacteria, e.g.gastrointestinal bacteria such as streptococci, e.g. S. faecium,Bacillus spp. such as B. subtilis and B. licheniformis, lactobacteria,Aspergillus spp., bifidogenic factors, or viruses such as indigenousvira, enterovira, bacteriophages, e.g. as vaccines, and fungi such asbaker's yeast, Saccharomyces cerevisiae and fungi imperfect. Apharmaceutical composition of the invention may also be used for thedelivery of active agents in specialized carriers such as liposomes,cydodextrines, nanoparticles, micelles and fats.

[0059] A further use for which a composition of the invention is suitedis the delivery of active substances to animals. Examples of such activesubstances for veterinary use are antiparasitics, corticosteroids,antibiotics, antiimflammatory agents, growth promoters and permittants,antifungals and antihelmintics.

[0060] A pharmaceutical composition of the invention is designed torelease the active substance in a controlled manner such as by a zeroorder release mechanism. Accordingly, the composition is especiallysuitable for a controlled release of an active substance. In the presentcontext the tern “controlled release” is used to designate a release adesired rate during a predetermined release period. Terms like“modified”, “delayed”, “sustained”, “prolonged”, “extended” etc. releaseare in the present context synonyms to the term “controlled release”.

[0061] In an embodiment of the invention, the active substance is apharmaceutically active powder. The powder typically has a particle sizeof from about 0.1 μm to about 500 μm, typically from about 0.5 μm toabout 300 μm, more typically from about 1 μm to about 200 μm, especiallyfrom about 5 μm to about 100 μm.

[0062] A pharmaceutical composition according to the invention is—due tothe possibility of designing the composition in such a manner that i) azero order release is obtained and ii) a controlled release during apredetermined time period is obtained—suitable for use for water solubleas well as slightly soluble or insoluble active substances. However, itis contemplated that a composition is also suitable for use when the atleast one therapeutically, prophylactically and/or diagnostically activesubstance has a solubility of at the most about 3 mg/ml such as, e.g. atthe most about 1 mg/ml, at the most about 0.1 mg/ml, at the most about0.05 mg/ml such as, e.g. at the most about 0.001 mg/ml in water atambient temperature and/or a prolonged release of the active substanceis desired in order to obtain i) a prolonged residence time within thebody after administration, ii) a reduced peak plasma concentration inorder to avoid peak related side effects, iii) reduced frequency ofadministration in order e.g. to obtain a better patient compliance, etc.

[0063] To this end it seems that substantially hydrophobic activesubstances tend to result in a decrease in the erosion rate of thematrix composition. Substantially hydrophilic or water-soluble activesubstances seem to have the opposite effect, i.e. they tend to result ina faster erosion of the matrix.

[0064] The at least one therapeutically, prophylactically and/ordiagnostically active substance will suitably be present in an amount ofup to about 70%, typically up to about 60% or up to about 50%, by weightof the matrix composition. An active substance content of about 60% iscontemplated to be the maximum content, which still allows for asufficient content of the polymer and, when relevant, thepharmaceutically acceptable excipient in the composition. The activesubstance may, on the other hand, be present in the composition in muchsmaller amounts, depending on the nature and potency of the activesubstance in question.

Pharmaceutically Acceptable Excipients

[0065] Difussion and Dissolution Adjusters

[0066] As already discussed above, it is important that a compositionaccording to the invention releases at least most of the activesubstance by a zero order release mechanism. One aspect of researchabout controlled-release delivery systems involves designing a system,which produces steady-state plasma drug levels. The release of activesubstance from such systems is also referred to as zero-order drugrelease kinetics. To meet this objective, numerous design variationshave been attempted, and their major controlling mechanisms includediffusion/dissolution.

[0067] The release rate of a dissolved or dispersed active substancefrom a polymeric matrix composition introduced in a specificenvironment, strongly depends on the nature of the diffusion andsorption processes involving the polymer/environment system and thepolymer/active substance system.

[0068] The active substance release data may be analysed using Eq. 1 andEq. 2 where M_(t)/M_(∞) is the fractional drug release, t is the releasetime, k is a kinetic constant characteristics of the drug/polymersystem, C_(d) is the tracer loading concentration and n is an exponentwhich characterisers the mechanism of release of the tracers.$\begin{matrix}{\frac{M_{t}}{M_{\infty}} = {k \cdot {t\quad}^{n}}} & \left( {{Eq}.\quad 1} \right) \\{\frac{M_{t}}{A \cdot {t}} = {n \cdot C_{d} \cdot k \cdot t^{\quad {n - 1}}}} & \left( {{Eq}.\quad 2} \right)\end{matrix}$

[0069] Clearly, a desirable mechanism for many applications is thatwhich leads to n=1. This characterizes zero-order behaviour. The tablebelow summarizes the general dependence of n on the diffusion mechanism.time dependence of Diffusinal release Overall Solute solute releaseExponent (n) diffusion mechanism rate (dM_(t)/d_(t)) 0.5 t^(−0.5)Fickian diffusion 0.5 < n < 1.0 Anomalous (non Fickian) t^(n−1)diffusion 1.0 Case II Transport Zero-order (time independent) releasen > 1.0 Super Case II transport t^(n−1)

[0070] In the case of PEO matrices, the solubility of the polymer canalter the characteristics of the penetrated layer, leading to differentbehaviours in systems presenting different dissolution features. Tocontrol the release of the active agent, there should be a balancebetween diffusion of the active agent and solubilization of the polymermatrix. The diffusivity of the drug through the matrix, the swelling ofthe polymer, and its solubilization rate may be biased by changing themolecular weight of the polymer or blending polymer fractions withdifferent molecular weights.

[0071] In the following is given examples on suitable excipients thatmay be added in order to adjust the balance between diffusion anddissolution so as to obtain zero order release rate. Thepharmaceutically acceptable excipients suitable for establishing theabove-mentioned desired balance, are in the present context also denotedDDAs (Diffusion and Dissolution Adjusters).

[0072] Thus, the matrix composition may also comprise one or morepharmaceutically acceptable excipients (DDAs). The function of the atleast one pharmaceutically acceptable excipient is to establish thedesired balance between on the one hand the diffusion rate of water intothe matrix composition and on the other hand the dissolution rate of thematrix composition in an aqueous medium such as, e.g., water. Asexplained above, a zero order release rate is obtained if that thediffusion rate of the aqueous medium into the matrix compositioncorresponds to about 100%±30% such as, e.g. about 100%±25%, about100%±20%, about 100%±15% or about 100%±10% or about 100% of thedissolution rate of the matrix composition. By the term “zero orderrelease” is meant that the release takes place so as to obtain a zeroorder release of at least about 60% w/w such as, e.g. at least about 65%w/w, at least about 70% w/w, at least about 75% w/w, at least about 80%w/w, at least about 85% w/w, at least about 90% w/w, at least about 95%w/w or at least about 97 or 98% w/w of the active substance from thepharmaceutical composition when subject to an in vitro dissolution testas described herein.

[0073] In general a test for diffusion of water into the matrixcomposition and a test for the dissolution of the matrix composition inan aqueous medium are performed using a matrix composition having thedesired shape and being prepared analogous to the matrix composition inthe final composition. This means that when the final composition isprepared by e.g. injection moulding then the matrix composition to betested with respect to diffusion and dissolution behaviour is alsoprepared by injection moulding.

[0074] There may be cases where it is not necessary to adjust the matrixcomposition by adding a pharmaceutically acceptable excipient. Suchcases are e.g. when the polymer employed in itself has the desiredproperties with respect to diffusion of water and dissolution ofpolymer.

[0075] In the experimental section herein examples are given showingthat it has been possible to obtain the desired zero order release whena pharmaceutically acceptable excipients has been incorporated into thematrix composition.

[0076] Without being bound by any theory it is contemplated that inthose cases where a slightly or insoluble active substance is employedthen it may be necessary to circumvent the effect from the activesubstance (with respect to diffusion and/or dissolution of the matrixcomposition) by adding a very soluble pharmaceutically acceptableexcipient. Accordingly, it is contemplated that when the at least onetherapeutically, prophylactically and/or diagnostically active substancehas a solubility of at the most about 3 mg/ml such as, e.g. at the mostabout 1 mg/ml, at the most about 0.1 mg/ml, at the most about 0.05 mg/mlsuch as, e.g. at the most about 0.001 mg/ml in water at ambienttemperature then the pharmaceutically acceptable excipient, if present,typically has a solubility of at least 1 mg/ml such as, e.g. at leastabout 3 mg/ml, at least about 5 mg/ml, at least about 10 mg/ml, at leastabout 25 mg/ml or at least about 50 mg/ml in water at ambienttemperature.

[0077] Vice versa, it is contemplated that in those cases where a verysoluble active substance is employed then it may be necessary tocircumvent the effect from the active substance (with respect todiffusion and/or dissolution of the matrix composition) by adding aslightly or insoluble pharmaceutically acceptable excipient.Accordingly, it is contemplated that when the at least onetherapeutically, prophylactically and/or diagnostically active substancehas a solubility of at least about 3 mg/ml such as, e.g., at least about5 mg/ml, at least about 10 mg/ml, at least about 20 mg/ml, at leastabout 50 mg/ml or at least about 100 mg/ml in water at ambienttemperature, then the pharmaceutically acceptable excipients typicallyhas a solubility of at the most about 3 mg/ml such as, e.g., at the mostabout 1 mg/ml, at the most about 0.1 mg/ml, at the most about 0.05 mg/mlsuch as, e.g. at the most about 0.001 mg/ml in water at ambienttemperature.

[0078] There may situations, however, where it also may be suitable toincorporate water-soluble substances (and/or water-insoluble substances)as DDA's irrespective of the solubility of the active substance.

[0079] Furthermore, in those cases where the active substance employedhas a low solubility in acidic medium, it is contemplated that aninorganic or organic base or substance having an alkaline reaction inaqueous environment is employed as a DDA.

[0080] Analogous, in those cases where the active substance employed hasa low solubility in alkaline medium, it is contemplated that aninorganic or organic acid or substance having an acidic reaction inaqueous environment is employed as a DDA.

[0081] However, other factors than the solubility in water play a rolein the erosion process and therefore there may be situations where suchfactors dominate the solubility factor and then the above-givencombinations may be of minor importance.

[0082] Suitable pharmaceutically acceptable excipients (DDAs) may beselected from the group consisting of inorganic acids, inorganic bases,inorganic salts, organic acids or bases and pharmaceutically acceptablesalts thereof, saccharides, oligosaccharides, polysaccharides, andcellulose and cellulose derivatives.

[0083] Altematively or additionally, a suitable pharmaceuticallyacceptable excipient is a mono-, di-, oligo, polycarboxylic acid oramino acids such as, e.g. acetic acid, succinic acid, citric acid,tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid,sorbic acid etc., aspartic acid, glutamic acid etc.

[0084] Examples of suitable organic acids include acetic acid/ethanoicacid, adipic acid, angelic acid, ascorbic acid/vitamin C, carbamic acid,cinnamic acid, citramalic acid, formic acid, fumaric acid, gallic acid,gentisic acid, glutaconic acid, glutaric acid, glyceric acid, glycolicacid, glyoxylic acid, lactic acid, levulinic acid, malonic acid,mandelic acid, oxalic acid, oxamic acid, pimelic acid, and pyruvic acid.

[0085] Examples of suitable inorganic acids include pyrophosphoric,glycerophosphoric, phosphoric such as ortho and meta phosphoric, boricacid, hydrochloric acid, and sulfuric acid.

[0086] Examples of suitable inorganic compounds include aluminium.

[0087] Examples of organic bases are p-nitrophenol, succinimide,benzenesulfonamide, 2-hydroxy-2cyclohexenone, imidazole, pyrrole,diethanolamine, ethyleneamine,tris (hydroxymethyl) aminomethane,hydroxylamine and derivates of amines, sodium citrate, aniline,hydrazine.

[0088] Examples of inorganic bases include aluminium oxide such as,e.g., aluminium oxide trihydrate, alumina, sodium hydroxide, potassiumhydroxide, calcium carbonate, ammonium carbonate, ammnonium hydroxide,KOH and the like.

[0089] Suitable pharmaceutically acceptable salts of an organic acid ise.g. an alkali metal salt or an alkaline earth metal salt such as, e.g.sodium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphateetc., potassium phosphate, potassium dihydrogenphosphate, potassiumhydrogenphosphate etc., calcium phosphate, dicalcium phosphate etc.,sodium sulfate, potassium sulfate, calcium sulfate, sodium carbonate,sodium hydrogencarbonate, potassium carbonate, potassiumhydrogencarbonate, calcium carbonate, magnesium carbonate etc., sodiumacetate, potassium acetate, calcium acetate, sodium succinate, potassiumsuccinate, calcium succinate, sodium citrate, potassium citrate, calciumcitrate, sodium tartrate, potassium tartrate, calcium tartrate etc.

[0090] A suitable inorganic salt for use in a matrix composition of theinvention is sodium chloride, potassium chloride, calcium chloride,magnesium chloride etc.

[0091] Examples of such excipients are glucose and othermonosaccharides, ribose, arabinose, xylose, lyxose, allose, altrose,inosito, glucose, sorbitol, mannose, gulose, idose, galactose, talose,mannitol, fructose, lactose, sucrose, and other disaccharides, dextrin,dextran or other polysaccharides, amylose, xylan, cellulose andcellulose derivatives such as, e.g. microcrystalline cellulose, methylcellulose, ethyl cellulose, ethylhydroxyethyl cellulose,ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, carboxymethyl cellulose, hydroxypropyl cellulose,hydroxymethylpropyl cellulose, hydroxypropylmethyl cellulose,amylopectin, pectin, starch, sodium starch etc., kaolin, bentonit,acacia, alginic acid, sodium alginate, calcium alginate, gelatin,dextrose, molasses, extract of Irish moss, panwar gum, ghatti gum,mucilage of isapol husk, veegum, glycollate, magnesium stearate, calciumstearate, stearic acid, talc, titanium dioxide, silicium dioxide, clays,croscarmellose, gums, agar etc.

[0092] Other Ingredients in the Matrix Composition

[0093] The matrix composition may also contain other excipients as well,e.g. in order to improve the technical properties of the matrixcomposition so that it may be easier to produce or in order to improvethe stability of the composition.

[0094] A suitable pharmaceutically acceptable excipient for use in amatrix composition of the invention may be selected from the groupconsisting of fillers, diluents, disintegrants, glidants, pH-adjustingagents, viscosity adjusting agents, solubility increasing or decreasingagents, osmotically active agents and solvents.

[0095] Suitable excipients include conventional tablet or capsuleexcipients. These excipients may be, for example, diluents such asdicalcium phosphate, calcium sulfate, lactose or sucrose or otherdisaccharides, cellulose, cellulose derivatives, kaolin, mannitol, drystarch, glucose or other monosaccharides, dextrin or otherpolysaccharides, sorbitol, inositol or mixtures thereof; binders such asacacia, sodium alginate, starch, gelatin, saccharides (includingglucose, sucrose, dextrose and lactose), molasses, extract of Irishmoss, panwar gum, ghatti gum, mucilage of isapol husk,carboxymethylcellulose, methylcellulose, veegum, larch arabolactan,polyethylene glycols, ethylcellulose, water, alcohols, waxes,polyvinylpyrrolidone such as, e.g., PVP K90 (may be used to improvemixing of the polymer with the other ingredients) or mixtures thereof;lubricants such as talc, magnesium stearate, calcium stearate, staericacid, hydrogenated vegetable oils, sodium benzoate, sodium chloride,leucine, carbowax 4000, magnesium lauryl sulfate, colloidal silicondioxide and mixtures thereof, disintegrants such as starches, clays,cellulose derivatives including crosscarmellose, gums, aligns, variouscombinations of hydrogencarbonates with weak acids (e.g. sodiumhydrogencarbonateitartaric acid or citric acid) crosprovidone, sodiumstarch glycolate, agar, cation exchange resins, citrus pulp, veegum HV,bentonite. or mixtures thereof; volatile solvents such as alcohols,including aqueous alcohols, petroleum benzine, acetone, ether ormixtures thereof; plasticizers such as sorbitol and glycerine; andothers such as cocoa butter, polyethylene glycols, e.g. with a molecularweight of about 1,000-500,000 daltons, typically about 1,000-100,000daltons, more typically 1,000-50,000 daltons, especially about1,000-10,000 daltons, in particular about 1,500-5,000 daltons, andmixtures thereof, hydrogenated vegetable oils, glycerinated gelatin ormixtures thereof.

[0096] The matrix composition may in addition include a cellulosederivative, e.g. a cellulose derivative selected from the groupconsisting of methylcellulose, carboxymethylcellulose and salts thereof,microcrystalline cellulose, ethylhydroxyethylcellulose,ethylmethylcellulose, hydroxyethylcellulose,hydroxyethylmethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxymethylcellulose andhydroxymethylpropylcellulose. Of these cellulose derivatives,hydroxypropylmethylcellulose and methylcellulose are preferred forincorporation in the matrix composition.

[0097] Furthermore, the matrix composition may comprise one or moreagents selected from the group consisting of sweetening agents,flavouring agents and colouring agents, in order to provide an elegantand palatable preparation. Examples of colouring agents are watersoluble FD&C dyes and mixtures thereof with corresponding lakes anddirect compression sugars such as Di-Pac from Amstar. In addition,coloured dye migration inhibitors such as tragacanth, acacia orattapulgite talc may be added. Specific examples include calciumcarbonate, chromium-cobalt-aluminium oxide, ferric ferrocyanide, ferricoxide, iron ammonium citrate, iron (III) oxide hydrated, iron oxides,magnesium carbonate, titanium dioxide.

[0098] Examples of suitable fillers are also dextrin, sucralfate,calcium hydroxyl-apatite, calcium phosphates and fatty acid salts suchas magnesium stearate.

[0099] The filler may be added in an amount so that the combination ofthe filler and the active substance comprises up to about 60%, typicallyup to about 50%, by weight of the first composition.

[0100] In order to soften the carrier system, a plasticziser may beincorporated in the composition. A suitable plasticizer is selected fromthe group consisting of phosphate esters; phthalate esters; amides;mineral oils; fatty adds and esters; fatty alcohols, vegetable oils andhydrogenated vegetable oils including acetylated hydrogenated cottonseedglyceride and acetylated hydrogenated soybean oil glycerides; acetyltributyl citrate, acetyl triethyl citrate, Castor oil, diacetylatedmonoglycerides, dipropylene glycol salicylate glycerin, glycerylcocoate, mono- and di-acetylated monoglycerides, nitrobenzene, carbondisulfide, β-naphtyl salicylate, phthalyl glycolate, diocyl phthalate;sorbitol, sorbitol glyceryl tricitrate; sucrose octaacetate;a-tocopheryl polyethylene glycol succinate, phosphate esters; phthalateesters; amides; mineral oils; fatty acids and esters; fatty alcohols;and vegetable oils, fatty alcohols including cetostearyl alcohol, cetylalcohol, stearyl alcohol, oleyl alcohol and myristyl alcohol; methylabietate, acetyl tributyl citrate, acetyl triethyl citrate, diisooctyladipate, amyl oleate, butyl ricinoleate, benzyl benzoate, butyl andglycol esters of fatty acids, butyl diglycol carbonate, butyl oleate,butyl stearate, di(beta-methoxyethyl) adipate, dibutyl sebacate, dibutyltartrate, diisobutyl adipate, dihexyl adipate, triethylene glycoldi(beta-ethyl butyrate), polyethylene glycol di(2-ethyl hexoate),diethylene glycol monolaurate, monomeric polyethylene ester,hydrogenated methyl ester of rosin, methoxyethyl oleate, butoxyethylstearate, butyl phthalyl butyl glycolate, glycerol tributyrate,triethylene glycol dipelargonate, beta-(p-tert-amyl phenoxy)ethanol,beta(p-tert-butytphenoxy)ethanol,beta-(p-teft-butytphenoxyethyl)acetate,bis(beta-p-tert-buthylphenoxydiethyl) ether, camphor, Cumar W-1, CumarMH-1, Cumar V-1, diamyl phthalate, (diamylphenoxy) ethanol, diphenyloxide, technical hydroabietyl alcohol, beckolin, benzenehexahydrochlonde, Clorafin 40, Piccolastic A-5, Piccalastic A-25, FlexolB400, Glycerol alfa-methyl alfa-phenyl ether, chlorinated naphthalene,HB-40, monoamylphthalate. Nevillac 10 o-nitrodiphenyl and Paracril 26.

[0101] Preferred anti-oxidative agents include TPGS due to surfactantproperties, BHA, BHT, t-butyl hydroquinone, calcium ascorbate, gallicacid, hydroquinone, maltol, octyl gallate, sodium bisulfite, sodiummetabisulfite, tocopherol and derivates thereof, citric acid, tartaricacid, and ascorbic acid. Other antioxidants include trivalentphosphorous like e.g phosphite, phenolic antioxidants, hydroxylamines,lactones such as substituted benzofuranones. Hindered phenols,thiosynergists and/or hindered amines are useful for the long-termstability for polymers, whereas the following antioxidants are suitablefor use also in situation where the active substance is subject tooxidation: acids (ascorbic acid, erythorbic acid, etidronic acid, gallicacid, hypophosphorous acid, nordihydroguairetic acid, propionic acidetc.), phenols (e.g. BHA, BHT, t-butyl hydroquinone, dodecyl gallate,octyl gallate, 1,3,5-trihydroxybenzene), organic and inorganic salts(calcium ascorbate, sodium ascorbate, sodium bisulphite, sodiummetabisulfite, sodium sulfite, potassium bisulphite, potassiummetabisulphite), esteres (calcium ascorbate, dilauryl thiodipropionate,dimyristyl thiodipropionate, distearyl thiodipropionate), pyranon(maltol), and vitamin E (tocopherol, D-α-tocopherol, DL-α-tocopherol,tocopheryl acetate, d-α-tocopheryl acetate, dl-α-tocopheryl acetate.However, other anti-oxidative agents known in the art may be usedaccording to the present invention.

pH Dependant Release

[0102] In some situations it may be convenient that the compositionreleases the active substance in a pH dependant manner. As described ine.g. WO 99/51208 a pH dependant release can be obtained by inclusion ofa so-called release rate modifier. The release rate modifier ispreferably selected from materials conventionally used in thepharmaceutical industry to produce enteric coatings. A number ofdifferent types of compounds suitable for use as enteric coatings areknown in the art; see e.g. Remington's Pharmmaceutical Sciences, 18^(th)Edition, 1990. Release modifiers may in particular be selected from oneof three general classes, namely cellulose derivatives, methacrylic acidpolymers and modified gelatine compounds. Preferred release modifiersinclude cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropyl methylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate, as well as methacrylic acidcopolyrmers. Modified gelatine compounds include gelatine treated withe.g. formaldehyde or glutaraldehyde.

[0103] Examples of commercially available polymers suitable as releasemodifiers are EUDRAGIT® L and EUDRAGIT® S, available from Röhm GmbH,Germany, and enteric coating agents available from Shin-Etsu ChemicalCo., Japan. The release modifier will typically be present in thecomposition in an amount of about 0.1-10%, based on the weight of thematrix, preferably about 0.5-4%, e.g. about 1-3%, such as about1.5-2.0%. If desired, a suitable mixture of more than one releasemodifier may be used in order to obtain a desired release profile in anygiven composition.

[0104] The release modifier enables a difference in release of theactive substance/erosion of the matrix dependant on pH.

Shape

[0105] The geometric form of the composition is important for theobtainment of the above-mentioned controlled zero order. Thus, in apreferred version of the invention, the pharmaceutical composition ofthe invention has a geometric shape, which enables a substantiallyconstant surface area to become exposed during erosion of the matrix.

[0106] In order to achieve a higher plasma concentration 510 hours afteradministration it is contemplated that a shape is suitable that exposesan increasing surface area during the first 1-3 hours and then exposes aconstant surface area. Examples of such shapes are given in FIG. 1B.

[0107] Specific examples of compositions with different shapes and sizesare: Length Diameter Vol Batch [mm] [mm] [mm³] 01-0034-042 7.5 5.05 15001-0035-042 6.0 5.64 150 01-0043-042 9.0 4.6 150

[0108] The following table describes formulations having a cylindricalform and oval openings in both ends Length Vol Batch [mm] [mm³]Longest/shortest diameter [mm] 01-0075-042 6.0 150 8.74 3.64 01-0076-0427.5 150 7.82 3.21

[0109] The coated compositions obtained were open at two opposite ends.The area for an open end is calculates as the volume/length of thecylindrical formulations.

[0110] The different strengths of the pharmaceutical composition arethen prepared based on a desired specific formulation, which has shownthe desired release duration. The release period is then secured bykeeping the same length in each strength formulation. Simply bydecreasing or increasing the exposed area with the same fold as thedesired increase or decrease, respectively, in the desired strengthcompared to the strength of the basis formulation different. In otherwords, the ratio between the amount of active substance and surface areaof the original basis formulation is constant in each individualstrength formulation.

[0111] However, minor corrections in the calculated area for theadditional strength formulations may be necessary in case the erosionrate (length of the eroded matrixitime unit) is dependent on the size ofthe area indicating non-linearity. However such non-linearity may betested by measuring the erosion rate individually with two differentexposed areas of the same matrix composition. In case the formulationsshow different dissolution rates, the ratio between the areas and therates may be calculated.

[0112] For instance, the present according to the present invention, theresults from Examples 1 to 4 demonstrates that Round 7.5 mm 5.05 mmdiameter 8 hours 0.94 mm/h Round 9 mm 4.6 mm diameter 9 hours 1.00 mm/hOval 6 mm 8.74/3.64 mm diam. 5.33 hours 1.12 mm/h Oval 7.5 mm 7.82/3.21mm diam. 6.49 hours 1.15 mm/h

[0113] Accordingly the release rate of the present matrix formulation isincreased with decreased area. The ratio between the two rates is 0.94:1and not 1:1 The ratio between the areas is 1.1:1 for the roundformulations.

[0114] These factors can be used to adjust the area and/or the length ofthe specific desired new strength when exactly the same matrix ispreferred in different pharmaceutical strengths.

[0115] Such increase in dissolution rate with decreasing exposed areamay be an advantage as it is expected that smaller areas in vivo mayresult in relative slower release.

[0116] In vitro, it is believed that when the area is decreased, thephysical factors of the dissolution parameters, (paddle rotation speed)might have a decreased erosion effect on the surface area bearing inmind the present shape of the formulation is a tube where the coat orwall of the tube remains intact during the erosion process.

[0117] The observation from the results mentioned above may relate tothe low solubility of carvedilol at high pH values. With smallerdiameters, more shell wall is present per mm² surface to protect deformulation from diffusion of the buffer solution.

[0118] In a still further embodiment, a formulation as disclosed inBatch 084 (12% load, 6 mm oval, 150 mm³ corresponding to 25 mg) having aerosion time of 5.6 hours and a length of 6 mm resulting in adissolution rate of approximately 1 mm/h (1.06 mm/h calculated) may beused for the preparation of dosages of 12.5 mg and 6,25 mg simplydecreasing the area of batch 084 by a factor 2 and 4 respectively.Furthermore, a 50 mg may be prepared by increasing the area with afactor 2 and in case the size of the formulation is being bigger thandesired, the load may be increased. Consequently, if the load isincreased to 18% from 12%, the area is increased 1.5 in order to providea 50 mg formulation.

[0119] In a further embodiment of the invention the design of aformulation may be made based on the dissolution of a differentformulation. If the desired rate is corresponding to the 6 mm ovalformulation as used in the clinical study disclosed herein having adissolution rate of 1 mm/h and the basis formulation has a dissolutionrate of 1.08. The calculated length would be 5.55 mm and the exposedarea may be adjusted accordingly to have the desired content.

[0120] Accordingly, preferred designs of a formulation wherein thedissolution rate is 1.08 in a oval 6 mm shape with a surface area of 25mm² and a load of Carvedilol and wherein the desired dissolutionduration is 5.5 hours is a formulation having a length of 5.5 mm

[0121] The surface areas may be adjusted to the desired content ofactive substance as illustrated above

[0122] Other designs according to the present invention for a 25 mgCarvedilol having a volume of 159 mm³ includes:

[0123] Surface area (one end) of 27.17 mm² and 5.85 mm length

[0124] Surface area (one end) of 25.00 mm² and 6.40 mm length

[0125] Designs for a 50 mg Carvedilol having a volume of 318 mm³includes:

[0126] Surface area (one end) of 45 mm² and 7 mm length

[0127] Surface area (one end) of 50 mm² and 6.4 mm length

[0128] Surface area (one end) of 55 mm² and 5.6 mm length

[0129] Designs for a 12,5 mg Carvedilol having a volume of 79.5 mm³includes

[0130] Surface area (one end) of 13.6 mm² and 5.85 mm length

[0131] Designs for a 6.25 mg Carvedilol having a volume of 39.75 mm³includes:

[0132] Surface area (one end) of 6.8 mm² and 5.85 mm length

[0133] Such small formulations may be prepared with a thicker shell forpatient compliance reasons. The final size of all the formulations maybe adjusted simply with adjusting the thickness of the shell for exampleby selecting the overall size of the 12.5 mg formulation.

Coating

[0134] The pharmaceutical composition may thus have the shape of acylindrical rod, which is provided with a coating, which issubstantially insoluble in and impermeable to fluids such as body fluidsduring the intended release period, the coating having an opening at oneor both ends. Polymers useful as coatings are preferably those, whichare possible to process by extrusion, solution or in the form of adispersion. Most preferred are those, which are available in a foodgrade or a pharmaceutical grade quality. Examples of such polymers arecellulose acetate, polyamide, polyethylene, polyethylene terephthalate,polypropylenem polyurethane, polyvinyl acetate, polyvinyl chloride,silicone rubber, latex, polyhydroxybutyrate, polyhydroxyvalerate,teflon, polylactic acid or polyglycolic acid and copolymers thereof,copolymers such as ethylene vinyl acetate (EVA),styrene-butadienestyrene (SBS) and styrene-isoprene-styrene (SIS).

[0135] The coating may also be a coating, which is substantially solublein and permeable to fluids such as body fluids during the intendedrelease period provided that the coating dissolves so much slower thanthe matrix composition that the coating remains intact until the matrixhas eroded and released the active substance. Examples of suitablepolymers include polyols as described herein.

[0136] The coating may further comprise any of the above-mentionedmatrix materials in a form, which erodes at a substantially slower ratethan the rest of the matrix. The coating may thus comprise a matrix ofone or more substantially water soluble crystalline polymers and,optionally, a non-ionic emulsifier, the coating being one which iseroded in the aqueous phase at a substantially slower rate than thematrix composition comprising the active substance, whereby asubstantially constant area of the matrix composition comprising theactive substance is exposed during erosion of the matrix composition,and whereby the coating is substantially eroded upon erosion of thematrix composition comprising the active substance. Such a coating willbe designed so that its longitudinal erosion rate is substantially thesame as the longitudinal erosion rate of the matrix, whereby the matrixand the coating will erode longitudinally towards the centre of thecomposition at substantially the same rate. Thus, when the matrixcomposition has been completely eroded by the aqueous medium, thecoating will also be substantially completely eroded. A matrixcomposition having such a coating has the obvious advantage of beingcompletely biodegraded upon release of the active substance. Such acoating will typically be a combination of a polyethylene glycol and amixture of, for example, polyethylene glycol 400 monostearate or anothernon-ionic emulsifier, and may also include a filler. The content of themixture of non-ionic emulsifiers and the filler in the coating will bedetermined in each particular case according to the characteristics,e.g. erosion rate and size, of the matrix comprising the activesubstance.

[0137] In an embodiment of the invention, the coating is one, whichdisintegrates or crumbles after erosion of the matrix. A coating of thistype will remain intact as long as it is supported by the matrixcontaining the active substance, but it lacks the ability to remainintact after erosion of the matrix, because it then disintegrates orcrumbles, so that it will not remain in e.g. a human or animal for anysignificant amount of time after the complete erosion of the matrix andthe release of the active substance.

[0138] The coating may also be an enteric coating employingmethacrylates, a co-polymer of methacrylate-galactomannan etc.

[0139] In an interesting embodiment, the controlled release compositionof the invention further comprises a coating having at least one openingexposing at least one surface of the matrix, the coating being one whichcrumbles and/or erodes upon exposure to the aqueous medium at a ratewhich is equal to or slower than the rate at which the matrix erodes inthe aqueous medium, allowing exposure of said surface of the matrix tothe aqueous medium to be controlled. Coatings of this type are describedin WO 95/22962, to which reference is made and which is incorporatedherein by reference.

[0140] These coatings comprise:

[0141] (a) a first cellulose derivative which has thermoplasticproperties and which is substantially insoluble in the aqueous medium inwhich the composition is to be used, e.g. an ethylcellulose such asethylcellulose having an ethoxyl content in the range of 44.5-52.5%, orcellulose acetate, cellulose propionate or cellulose nitrate;

[0142] and at least one of:

[0143] (b) a second cellulose derivative which is soluble or dispersiblein water, e.g. a cellulose derivative selected from the group consistingof methylcellulose, carboxymethylcellulose and salts thereof, celluloseacetate phthalate, microcrystalline cellulose,ethylhydroxyethylcellulose, ethylmethylcellulose, hydroxyethylcellulose,hydroxyethylmethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxymethylcellulose andhydroxymethylpropylcellulose;

[0144] (c) a plasticizer, e.g. selected from the group consisting ofphosphate esters; phthalate esters; amides; mineral oils; fatty acidsand esters thereof with polyethylene glycol, glycerin or sugars; fattyalcohols and ethers thereof with polyethylene glycol, glycerin orsugars; and vegetable oils; or a non-ionic surfactant; and

[0145] (d) a filler, e.g. selected from conventional tablet or capsuleexcipients such as diluents, binders, lubricants and disintegrants.

[0146] The use of a plasticizer will often be desirable inorder toimprove the processibility of the ethylcellulose or the first cellulosederivative. The plasticizer may also be a non-ionic surfactant, e.g. anon-ionic surfactant selected from the group consisting of diacetylatedmonoglycerides, diethylene glycol monostearate, ethylene glycolmonostearate, glyceryl monooleate, glyceryl monostearate, propyleneglycol monostearate, macrogol esters, macrogol stearate 400, macrogolstearate 2000, polyoxyethylene 50 stearate, macrogol ethers,cetomacrogol 1000, lauromacrogols, nonoxinols, octocinols, tyloxapol,poloxamers, polyvinyl alcohols, polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, sorbitanmonolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitantristearate and sucrose esters; nitrobenzene, carbon disulfide,β-naphtyl salicylate, phthalyl glycolate, dioctyl phthalate.

[0147] Other suitable plasticizers appear from EP-B0 746 310 to whichreference is made.

Pharmaceutical Composition

[0148] As mentioned above a pharmaceutical composition according to theinvention is a coated matrix composition from which the active substanceis released in by a zero order release mechanism.

[0149] A composition according to the invention containing a drugsubstance is typically for oral administration and may be in the form ofa tablet or a capsule or in the form of a multiple unit dosage form. Dueto the possibility of controlling the release rate of the activesubstance the composition may be adapted for oral administration 1-4times a day, normally 1-4 times daily such as 1-3 times, 1-2 times or 1times daily. The technology may also provide compositions foradministration only once or twice daily. In the present context the term“once daily” is intended to mean that it is only necessary to administerthe pharmaceutical composition once a day in order to obtain a suitabletherapeutic and/or prophylactic response; however, any administrationmay comprise co-administration of more than one dosage unit, such as,e.g. 2-4 dosage units if the amount of active substance required may notbe formulated in only one composition or if a composition of a smallersize is preferred.

[0150] The dosage of the active substance depends on the particularsubstance, the age, weight condition etc. of the human or animal thatwill be treated with the composition etc. All such factors are wellknown to a person skilled in the art.

[0151] The controlled release of the active substance is caused byerosion at a substantially constant rate of a surface or surfaces of thecomposition

[0152] The rate at which the active substance is released from thematrix is a predetermined rate, i.e. a rate, which is controllable overa certain period of time. The release rate required in each particularinstance may inter alia depend on the amount of active substance to bereleased for it to exert the desired effect, as well as on the overalldosage of the active substance contained in the matrix. The substance ofwhich the matrix is composed and the distribution of the activesubstance in the matrix may therefore be selected according to one ormore of these criteria to ensure the desired level of release of theactive substance.

[0153] Due to the controlled release of the active substance obtainablefrom the pharmaceutical composition of the invention, it is possible toobtain a substantially constant rate of release of the active substanceover a specific period of time, corresponding to the dosage necessaryfor the treatment in question, so that adherence to a strict dosageregimen, e.g. requiring administration of a drug at set intervals up toseveral times a day, may be dispensed with.

[0154] Furthermore, it is possible to include two or more differentactive substances in the pharmaceutical composition of the invention,and the two or more different active substances may be adapted to bereleased at different concentrations and/or intervals, thus making iteasier for patients to follow a prescribed regimen.

[0155] An additional advantage of a pharmaceutical composition of theinvention, compared to other known controlled release compositions, isthat it may be produced by relatively simple and inexpensive methods.

[0156] Furthermore, a pharmaceutical composition according to theinvention allows for the incorporation of high concentrations of theactive substance relative to the size of the delivery system. This isobviously a great advantage, notably when the composition is to be usedfor the delivery of a therapeutically, prophylactically and/ordiagnostically active substance, since it allows for the delivery of therequired amount of the active substance without the size of thecomposition being unnecessarily large. In addition, sparingly soluble ornon-soluble active substances may be readily incorporated into acomposition of the invention. A composition of the invention may thus beused for the delivery of, for example, sparingly soluble or non-solublepharmaceutical powders which can otherwise be difficult to administer.

[0157] As mentioned above, the release of the active substance from thepharmaceutical composition corresponds to a substantially zero orderrelease determined by in vitro dissolution test according to USP. Thesubstantially zero order release is obtained in a time period of atleast 1 hours such as, e.g. at least 2 hours, at least 3 hours, at least4 hours or at least 5 hours, or in a time period of at least 5 hourssuch as, e.g. at least 6 hours, at least 7 hours, at least 8 hours, atleast 9 hours or at least 10 hours.

Multiple Units Composition

[0158] The pharmaceutical composition according to the invention mayfurthermore be used in the preparation of a multiple unitspharmaceutical composition, e.g. in the form of a capsule or tablet. Amultiple units pharmaceutical composition is a composition, whichcomprises a multiplicity of individual units in such a form that theindividual units will be made available upon disintegration of thecomposition, typically a capsule or tablet, in the stomach of humans oranimals ingesting said composition. Thus, in this case, at least some ofthe individual units in said multiple units pharmaceutical compositionwill consist of the composition of the invention, the individual unitsbeing of a size, which allows them to be incorporated into such acomposition.

Stability

[0159] In order to improve the stability of a composition according tothe invention, the composition may optionally comprise a stabilizingagent.

[0160] In the present context, the terms “stability” and “stabilizingagent” are employed to encompass one or more of the following:

[0161] Stability with respect to the final composition:

[0162] i) stablility with respect to the physical stability of thecomposition (appearance, color, strength, etc

[0163] ii) stability with respect to in vitro dissolution behaviour ofthe active substance from the composition

[0164] Stablility of the individual components:

[0165] iii) stablility with respect to the chemical stability of theactive substance (degradation of the active substance toother—normally—unwanted products)

[0166] iv) stability with respect to the form the active substance hasin the composition; normally, the active substance is dissolved(molecularly dispersed) in the polymer as a solid dispersion. In suchcases precipitation or otherwise formation of crystals of the activesubstance in the composition is an indication of a stability problem.

[0167] v) physical and chemical stability of the pharmaceuticallyacceptable polymer employed as component ii).

[0168] Normally, stability is considered under specific storage and testconditions. In the present context, a stable composition is acomposition that does not change (with respect to a specific property)more than 20% within a time period of at least 2 weeks (when physicalparameters are considered) or a period of at least 3 months (whenchemical parameters are considers). Specific conditions appear from thepatent claims herein.

[0169] Many crystalline, therapeutically active substances have a veryslight solubility in aqueous medium such as, e.g., body fluids. It iswell known that changing a crystalline compound into its amorphous statewill substantially increase the aqueous solubility of the compound. Theamorphous state of an active substance may be obtained by melting theactive substance, holding it in the molten state for a certain period oftime and then cooling it to an amorphous solid. Such a method isespecially suitable for active substances that can produce stableamorphous solids and which are not degraded by the heating step.

[0170] Accordingly, for active substances having a very low watersolubility (e.g. at the most about 3 mg/ml as defined herein) it may beappropriate to present the active substance at least partly on amorphousform in the composition. However, due to the inherent instability of theamorphos state it is often necessary to provide suitable conditions inthe composition for improved stability as well as to provide suitablestorage conditions. Irrespective of the release mechanism of the activesubstance from the composition, the present inventors have foundthat—when active substances with a low water solubility is employed—asuitable stable pharmaceutical compositions for oral use is acomposition comprising a solid dispersion of component i) and ii)

[0171] i) being at least one therapeutically, prophylactically and/ordiagnostically active substance, which at least partially is in anamorphous form,

[0172] ii) being a pharmaceutically acceptable polymer that hasplasticizing properties and which has a melting point or meltinginterval of a temperature of at the most 200° C., and, optionally, astabilizing agent.

[0173] Typically, the at least one therapeutically, prophylacticallyand/or diagnostically active substance has a water solubility of at themost 3 mg/ml at 25° C. such as, e.g. at the most about 2 mg/ml, at themost about 1 mg/ml, and the concentration of the active substance in thecomposition corresponds to a concentration of at the most the saturatedconcentration in component ii) at a temperature corresponding to themelting point or the lowest end point of the melting interval ofcomponent ii) optionally together with component iii).

[0174] In a further aspect, the invention relates to compositions asdescribed above.

[0175] To this end, the present inventors have found that it is ofutmost importance in order to obtain a stable composition that theactive ingredient is present in the solid dispersion in a suitableconcentration that makes it possible to prevent formation of anyunwanted precipitates during storage under normal conditions. In thepresent context it is especially of interest to avoid formation ofcrystals of the active substance.

[0176] Normally supersaturated systems (i.e. systems wherein theconcentration of a given substance in a medium is larger than thesolubility in the medium) are instable systems that after a certain timeperiod will lead to precipitation of the substance in the medium.

[0177] In a saturated system, which is a stable system, an equilibriumbetween solid and dissolved substance will take place. In systems wherethe active substance is present in dissolved form and the concentrationof the substance is well below the solubility normally no change withrespect to formation of precipitates will take place (unless thesubstance is degraded to insoluble products etc.). A dissolved systemmay therefore be regarded as a stable system. However, in practice thesituation is often much more complex and it is normally necessary tostabilize even dissolved system by use of different methods.

[0178] An important feature of the invention is that the activesubstance is converted to and stabilized in its amorphous form as asolid dispersion. The amorphous state and/or the solid dispersion isstabilized either by a very careful choice of the concentration of theactive substance in the composition and/or by addition of suitablestabilizing agents acting by stabilizing one or more of the conditionsmentioned above under items i) to v).

[0179] In a specific embodiment, the pharmaceutically acceptable polymeremployed as component ii) is a polyethylene oxide having a molecularweight of at least about 20,000 in crystalline and/or amorphous form ora mixture such polymers. More details on suitable polymers are disclosedherein. The solubility of a particular active substance in PEO dependsinter alia on the quality and the molecular weight of the PEO employed.Thus, in order to determine a suitable concentration of the activesubstance in a composition of the invention it is necessary to determinethe solubility of the active substance in the PEO (or other polymersemployed) in question. The solubility is normally determined at atemperature that corresponds to the melting or softening point of thePEO in question and the solubility determined is the saturationsolubility. A person skilled in the art knows how to determine thesolubility of a specific substance in a specific polymer.

[0180] Normally, when preparing a composition according to the inventionheating is employed for an injection moulding process. During heating ithas been observed that PEO in various qualities forms free radicals thatresults in the formation of inter alia formaldehyde and formic acid.These products may often lead to further degradation e.g. of the activesubstance present in the composition and it is therefore necessary totake the necessary precautions in this respect. Oxidative free radicalsdegradation by hydroperoxides can be catalysed by certain transitionmetal ions, especially those of copper, cobalt and manganese. Thus,employment of PEO qualities devoid of or only containing a very smallamount of such transition metal ions may improve stability. Anotherpossibility is to use component ii) in a quality that ensures that freeradicals formed, if any, do not significantly increase the degradationof the active substance in the composition. Such a quality could e.g. bea quality containing an antioxidant that functions by preventing theformation of free radical during heating or by scavenging any freeradicals formed. Another possibility is to add such antioxidant to theformulation before any heating takes place.

[0181] Suitable qualities include PEO 200,000 NF or LF from DowChemicals.

[0182] A composition according to the invention may therefore furthercomprise one or more antioxidants that inhibits the formation ofperoxides and/or inactivates any peroxides present.

[0183] Suitable antioxidants for use includes beta-caroten (a vitamin Aprecursor), ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole,butylated hydroxytoluene, hypophosphorous acid, monothioglycerol,potassium metabisulfite, sodium metabisulfite, propyl gallate, sodiumformaldehylde sulfoxylate, sodium thiosulfate, sulfur dioxide,tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or othertocopherol derivatives, sulfides, phosphine etc. Other suitableantioxidants are described herein.

[0184] Another measure to reduce any oxidation during processing is toemploy nitrogen purges during manufacturing.

Preparation

[0185] The delivery system as well as the first composition of theinvention may be produced by various methods which are either known perse in the pharmaceutical industry or which, for example, are used in theproductiori of polymer-based materials, depending upon the desiredembodiment and the materials employed in the composition in question. Asmentioned above, one advantage of the composition according to theinvention is that it may be produced by methods, which are relativelysimple and inexpensive.

[0186] A pharmaceutical composition may be produced by, for example,co-extrusion of the coating with the matrix composition and the activesubstance, extrusion and dip coating, injection moulding and dipcoating, or by extrusion or injection moulding and solvent coating byspraying or dipping.

[0187] For further details reference is made to the experimental sectionherein.

Method for Controlling the Release

[0188] As mentioned above, the invention also relates to a method forcontrolling the release of a therapeutically, prophylactically and/ordiagnostically active substance from a pharmaceutical composition. Tothis end all details and particulars described above under thecomposition aspect applies mutatis mutandi to the method aspect and anyother aspect.

[0189] The invention is further illustrated in the figures and in thefollowing non-limiting examples.

[0190]FIG. 1 is a plug holder suitable for use when determiningdiffusion and dissolution rate. A stopper on the right seals the plugholder, and,the swelling layer is formed on the left side on the plug.

[0191]FIG. 2 is the results from pilot study of Example 5.

[0192]FIG. 3 shows the DSC of carvedilol as starting material and a peakis observed corresponding to that carvedilol is employed in crystallineform.

[0193]FIG. 4-5 are the DSCs of PEO 200,000 and citric acid,respectively, and show that the substances are employed as crystals.

[0194]FIG. 6 shows that PEO+citric acid only has one peak indicatingthat citric acid is present on amorphous or dissolved form or possiblein a different crystalline form. Carvedilol when admixed with PEO andcitric acid maintain at least some of its crystallinity (no heating hastaken place).

[0195]FIG. 7 shows DSC's of compositions according to the invention. Nopeak is present for carvedilol indicating the carvedilol is present inamorphous form. Storage of the compositions as mentioned above for about1 month did not show any substantial difference in the DSC pattem.

[0196]FIG. 8 shows the dissolution profile relating to a composition ofExample 8 denoted 0069; the dissolution has been determined in FaSSIFmedium (cf. Dressmann et al. J. Pharm. Sci. 11 Suppl. 2 (2000) ppS73-S80.

[0197]FIG. 9 shows the dissolution profile relating to a composition ofExample 8 denoted 0069; the dissolution has been determined in FeSSIFmedium (cf. Dressmann et al. J. Pharm. Sci. 11 Suppl. 2 (2000) ppS73-S80.

[0198]FIG. 10 shows the dissolution profile relating to a composition ofExample 8 denoted 0069; the dissolution has been determined after 26days storage at 30°0 C. and 60% RH.

[0199]FIG. 11 is a suitable shape for an opioid composition. Suitablevalues are e.g. a=3 mm, b=4.5 mm, c=1.5 mm and d=9 mm; a=3 mm, b=4.6 mm,c=2 mm and d=9 mm; a=2.3 mm, b=5.3 mm, c=1.5 mm and d=7.5 mm; or a=3.4mm, b=5.1 mm, c=2 mm and d=7.5 mm

[0200]FIG. 12 is the dissolution profile from the composition of Example9.

[0201]FIG. 13 (1A, 1B, 2A and 2B) shows the dissolution profiles fromthe compositions of Example 10.

[0202]FIG. 14 shows the plasma concentration vs. time profile for theclinical study on healthy volunteers reported in Example 11.

[0203]FIG. 15 shows the plasma concentration vs. time profile for theclinical study in phase II reported in Example 11.

Methods Diffusion/Dissolution Studies

[0204] Method for Determination of Dissolution Rate of the Matrix

[0205] A composition according to the invention has properties thatensure that the diffusion rate of water into the polymer matrixsubstantially corresponds to the dissolution rate of the polymer matrixcomposition into the aqueous medium. In the following is given a simplemethod to test these conditions.

[0206] The polymers that are suitable for use according to the presentinvention and which are sufficiently hydrophilic are water-soluble. Whencontacted with water, a sharp advancing waterfront divides the intactand not penetrated matrix from a swollen front. Under stationaryconditions, a constant thickness surface layer is formed by the swollenpolymer and by a high concentration of polymer in solution.

[0207] In fact, once the hydrodynamic external conditions are defined, astationary state is reached where the rate of penetration of the movingboundary equals the rate of removal of the polymer at the externalsurface.

[0208] The time lapse until the quasi-stationary state is reached iscalled swelling time. At steady state, the dissolution rate is constantand can be defined equally by either the velocity of the retractingfront of the polymer or the velocity of the front separating the purepenetrate and the liquid dissolving sublayer. Thus, both fronts aresynchronized.

[0209] When the dissolution rate equals the penetration rate (i.e. thediffusion rate) a constant thickness surface layer should be observed.The dissolving layer evolution during water conditioning should reflectthe different dissolution characteristics of the materials employed. Thesurface layer thickness is measured as a function of time.

[0210] In order to measure the diffusion rates of water, samples may beprepared in the form of plugs fitting to the sample holder (e.g. 2 mm, 4mm, 6 mm, 7.5 mm and 12 mm long and preferable with the same shape andvolume as the desired dosage unit). The sample holder is prepared bytranslucent glass in a tubular shape and with noticeable marks indicatedwith a specific distance.

[0211] The test proceeds as follows: Place 1 plug incorporated into theglass tube in a vessel—optionally with a water soluble dye (e.g.Cu²⁺)—and the plug/glass tube is placed in a dissolution apparatus e.g.according to monograph: USP 24, page 1941-1950, which is herebyincorporated by reference (see FIG. 1). By employment of the USP methodit is possible to determine the diffusion rate as well as thedissolution rate in the same experiment. The copper ions areblue-coloured so they are visually detectable and due to the metricscale on the tube, the diffusion rate can be calculated (unit islength/time). The dissolution rate is determined by determining theamount of substance (e.g. active substance) released and at the sametime determining the length of the matrix composition that has beeneroded. Thus, the dissolution rate is also in length/time units. As thedissolution profile easily can be obtained from the data measured, asimple means for the determination of whether the release follows zeroorder is to investigate the dissolution profile and see whetherlinearity is present.

[0212] Agitation is provided, and the length of the front of matrix ismeasured at desired time intervals as a function of time. Themeasurement may be a simple visual identification of the marks on theglass tube.

[0213] When the dissolution rate equals the penetration rate a constantthickness surface layer is observed. The different dissolving layers indifferent matrices obtained during the water contact, reflect thedifferent dissolution characteristics of the matrix. The thickness ofthe surface layer as a function of time is then compared. The specificaqueous medium may be selected individually.

Dissolution Test

[0214] Dissolution tests were performed in accordance with the USP 24,NF 19, (711) Dissolution, Apparatus 2 equipped with a paddle. Thedissolution medium was 0.1 N hydrochloric acid during the first 120 min,which was then substituted with a buffer solution pH 6.8. The volume ofthe dissolution medium was 1000 ml and the rotation speed of the paddlewas 120 rpm during the first 120 min and then 50 rpm. Samples werewithdrawn at suitable time intervals and analyzed for content of activesubstance by means of UV spectrometry at a wavelength of 284 nm.

EXAMPLES A General Method for the Preparation of a Controlled ReleaseComposition is Described Below Preparation of the Matrix Composition

[0215] An accurate amount of the polymer (i.e. in the examples below:the polyethylene oxide) is loaded into a MTI mixer followed by anaccurate amount of the active substance and of the pharmaceuticallyacceptable excipients(s), if any. The mixing is performed at 2050/1450rpm and at a time period of 10 min+4 min+short final spinning. At thestart of the mixing the temperature is about 19° C. (the first timeperiod) and the final temperature of the mixture is about 52° C. (thesecond and third time period). The mixture is then allowed to cool toroom temperature and is ready to be fed into an injection mouldingmachine.

Preparation of the Coating Composition

[0216] The coating composition was prepared by first adding thehydroxymethylcellulose then cetostearyl alcohol, and finally thetitanium dioxide to an MTI-Mixer at a temperature about 21° C. Aftermixing for nearly 9 min at 1000 rpm (I: 0.9 A) the mixer was stopped(temperature about 46° C.) and the adhered material manuallyincorporated into the mixture. The mixture was left to cool for about 10minutes. The mixing is then finalized with a short high-speed mix inorder to minimize lumps formation. The mixture was then allowed to coolto room temperature, after which it had a suitable consistency for beingfed into an injection moulding machine.

Example of Coat Composition

[0217] Batch: 58-014-01-013 amount Weight % Batch Material (g) (g) step79 991207-A Ethocel 632 632 1 20 990426-B Cetylstearyl Alkohol 160 160.12 1 97051301 TiO₂ 8 8.0 3 100 total 800 800.1

[0218] The final dosage units may be prepared according to two differentmethods. In one method, the coat and the matrix moulded individuallyfollowed by a manually incorporation of the moulded matrix plug into themoulded coat. The moulding machine used is an Arburg Allrounder 220 S250/60.

[0219] In the second method, the coat and matrix are moulded in oneprocess where the coat is moulded in a first step and the matrix ismoulded directly into the coat in a second step. The moulding machineused is Arburg Allrounder 420 V 800-60/35.

[0220] The following table describes formulations having a cylindricalform and circular openings in both ends. Length Diameter Vol Batch [mm][mm] [mm³] 01-0034-042 7.5 5.05 150 01-0035-042 6.0 5.64 150 01-0043-0429.0 4.6 150

[0221] The following table describes formulations having a cylindricalform and oval openings in both ends Length Vol Batch [mm] [mm³]Longest/shortest diameter [mm] 01-0075-042 6.0 150 8.74 3.64 01-0076-0427.5 150 7.82 3.21

[0222] The coated compositions obtained were open at two opposite ends.The area for an open end is calculates as the volume/length of thecylindrical formulations.

Example 1 Preparation of a Pharmaceutical Composition ComprisingCarvedilol as an Active Substance

[0223] A composition (plug batch No. 01-0045-042), formulation batch No.01-0034 042 according to the invention was prepared from the followingingredients: No Raw materials Reference: 1 PEO 200,000 S-Ega40200;USP24-NF19 2000 p. 2497 2 Carvedilol Ph. Eur. 3rd Ed. 2000 p.359 3Citric Acid Ph. Eur. 3rd Ed. 1997 p.645 Matrix % w/w Polyethylene oxide64.6 Carvedilol (Cipla) 30 Citric acid 5.4

[0224] The coating and the matrix were prepared as described above. Onedosage form contains 50 mg carvedilol. The composition was 7.5 mm long.

[0225] The composition was subjected to the dissolution test describedabove. The following results were obtained: dissolved carvedilol Time(h) (% w/w of the coated composition) 0 0 1 14.1 2 27.1 3 39.3 4 49.9 560.7 6 72.5 7 85.0 8 99.7

[0226] The solution profile corresponds to a zero order release ofcarvedilol from the composition.

Example 2 Preparation of an Oval Shaped Pharmaceutical CompositionComprising Carvedilol as an Active Substance

[0227] A complsition (batch No. 01-0076-042) according to the inventionwas prepared from the following ingredients: Matrix % w/w Polyethyleneoxide 64.6 Carvedilol (Cipla) 30 Citric acid  5.4

[0228] The coating and the matrix were prepared as described above. Onedosis form contain 50 mg carvedilol. The composition was 7.5 mm long andhad an oval cross sectional shape.

[0229] The composition was subjected to the dissolution test describedabove. The following results were obtained: dissolved carvedilol Time(h) (% w/w of the coated composition) 0 0 1 15.9 2 30.1 3 46.2 4 62.2 577.61 6 92.4

[0230] The dissolution profile corresponds to a zero order release ofcarvedilol from the composition.

Example 3 Preparation of a Pharmaceutical Composition ComprisingCarvedilol as an Active Substace

[0231] A composition (plug batch No. 01-0044-042, dosage unit batch No.01-0043 042) according to the invention was prepared from the followingingredients: Matrix % w/w Polyethylene oxide 64.6 Carvedilol (Cipla) 30Citric acid 5.4

[0232] The coating and the matrix were prepared as described above. Onedosage form contains 50 mg carvedilol. The composition was 9 mm long.

[0233] The composition was subjected to the dissolution test describedabove. The following results were obtained: dissolved carvedilol Time(h) (% w/w of the coated composition) 0 0 1 13.2 2 22.5 3 33.2 4 44.7 556.2 6 67.0 7 77.2 8 88.1 9 98.6

[0234] The dissolution profile corresponds to a zero order release ofcarvedilol from the composition.

Example 4 Preparation of a Pharmaceutical Composition ComprisingCarvedilol as an Active Substance

[0235] A composition (batch No. 01-0075-042) according to the inventionwas prepared from the following ingredients: Matrix % w/w Polyethyleneoxide 64.6 Carvedilol (Cipla) 30 Citric acid 5.4

[0236] The coating and the matrix were prepared as described above. Onedosage unit form contains 50 mg carvedilol. The composition was 6 mmlong and had an oval shape.

[0237] The composition was subjected to the dissolution test describedabove. The following results were obtained: dissolved carvedilol Time(h) (% w/w of the coated composition) 0 0 1 17.0 2 35.1 3 55.1 4 74.7 593.8

[0238] The dissolution profile corresponds to a zero order release ofcarvedilol from the composition.

Example 4A Preparation of a Pharmaceutical Composition ComprisingCarvedilol as an Active Substance

[0239] A composition (batch No. EC-042-211) according to the inventionwas prepared from the following ingredients: Matrix % w/w Polyethyleneoxide 86 Carvedilol (Cipla) 14

[0240] The coating and the matrix were prepared as described above. Onedosage unit form contains 25 mg carvedilol. The composition was 12 mmlong and had circular end surfaces.

[0241] The composition was subjected to the dissolution test describedabove. The following results were obtained:

[0242] Dissolved carvedilol (% w/w of the coated composition) from hour1 to 15 hours dissolved carvedilol Time (h) (% w/w of the coatedcomposition) 1 12.4 2 21.6 3 29.2 4 35.4 5 40.0 6 44.5 7 49.4 8 54.3 959.4 10 64.6 11 70.6 12 75.5 13 79.8 14 84.1 15 88.7 16 92.6 17 94.6

[0243] The dissolution profile corresponds to a zero order release ofcarvedilol from the composition.

Example 5 Pilot Phase I Studies in Health Volunteers EmployingCarvedilol Compositions According to the Invention

[0244] Carvedilol has emerged as one of the important and promisingdrugs for cardiovascular diseases including hypertension and congestiveheart failure, and results in a noticeable improvement of survival ratesin patients with chronic cardiac insufficiency. To further optimize thetreatment, Carvedilol Egalet® has been developed as a once dailycomposition.

[0245] Carvedilol is currently marketed as an immediate releaseformulation only in 3,125 mg, 6,25 mg, 12,5 mg, 25 mg and 50 mg tablets.Only the 6,25 mg and 25 mg application form is available throughout theEU whilst of the other strengths some are missing in certain memberstates. A 25 mg immediate release application form may be used as areference.

[0246] Carvedilol is registered for the following indications:

[0247] Hypertension

[0248] Chronic cardiac insufficiency

[0249] Angina pectoris

[0250] Carvedilol Egalet® is developed for long-term treatment ofhypertension and is therefore developed for a maintenance dosage.However, the present invention encompasses other dosages where acontrolled delivery is desired.

[0251] The expected advantages offered by the Carvedilol Egalet®compared to the immediate release formulation include:

[0252] i) Reduced standard deviation and thus, a more predictableconcentration in plasma.

[0253] ii) A dose regimen with lower frequency of administration andthereby potentially improvement of patient compliance.

[0254] For patients with cardiac insufficiency, it is recommended totake Carvedilol with a meal to delay absorption and thereby avoidadverse reactions. Carvedilol Egalet® offers the advantage of reducedC_(max), even if taken fasting. (Latest studies CL-EG-pilot-1 andCL-EG-pilot-02 shows that C_(max) is only slightly as high as for 25 mgCarvedilol IR).

[0255] Patients with hypertension have a well-described low compliance,presumably because there are no recognizable symptoms connected with thecondition. Compliance with a once-daily regimen is higher and thereforeoffers a therapeutic advantage. Recommendations for the use ofCarvedilol vary between countries.

[0256] An evaluation of Carvedilol in “Drugs” from 1997 lists in thesummary under Dosage and Administration “A dosage of Carvedilol 12.5 mgonce daily for 2 days, increased to 25 mg daily thereafter and increasedto 50 mg once daily after 2 weeks if necessary, is recommended forpatients with mild to moderate hypertension”.

[0257] According to the American Physician's Desk Reference (PDR) 2000,Carvedilol should be prescribed twice daily for all indications.

[0258] According to the German Drug Listing (Rote Liste 2001 forDilatrend®), Carvedilol should be prescribed twice daily for cardiacinsufficiency and angina pectoris, and once to twice daily forhypertension with a maximum dose of 2×25 mg.

[0259] According to “Drugs, Fact and Compariso”, Carvedilol isprescribed twice daily for hypertension. In all countries, the maximumdaily dose is 25 mg b.i.d., and it is against this dose and frequencythat Carvedilol Egalet is tested herein.

Composition of Carvedilol Egalet

[0260] In the development work on Carvedilol Egalet®, differentcompositions of matrix have been tested, i.e. the load of drug has beenvaried.

[0261] In Table 1 below is given the final composition of the coatedcomposition used in the pilot studies. The individual compositionemployed in Pilot tests III, Iv and V corresponds to the compositions ofExamples 1-4. TABLE 1 Composition of Carvedilol Egalet ® Reference toIngredients Percentage Function standards Active substance Carvedilol32% Active compound Cipla Excipients Citric Acid  5% Matrix Ph. Eur.Polyethylene Oxide 63% Matrix USP (PEO 200000) Ethylcellulose 79% ShellPh. Eur Ceto-stearyl alcohol 19.8%   Shell Ph. Eur Titanium dioxide  1%Shell Ph. Eur Ferro Oxide 0,2%  Colouring USP

Pharmacodynamics

[0262] There are several pharmacodynamics issues to be described for theCarvedilol Egalet®. The following is a list of issues and theconsiderations regarding their testing.

[0263] 01. Bioavailability

[0264] a) Rate and extent of absorption

[0265] b) Fluctuations in drug concentration

[0266] c) Variability arising from the formulation

[0267] d) Dose proportionality

[0268] e) Risk of unexpected release characteristics

[0269] 2. Factors influencing the performance of a modified drugformulation

[0270] f) GI function

[0271] g) Diumal rhythm

[0272] 3. Stereoisomers

[0273] Ad a-c Absorption, fluctuations and variability:

[0274] These characteristics are described by the pharmacokineticstudies already conducted and will be further confirmed in studiesplanned.

[0275] a. Absorption

[0276] There is no literature on slow release formulations ofCarvedilol. One study has been identified on in-vivo absorption ofCarvedilol formulated in timed-release capsules. This study by Nolte etal found absorption throughout the GI tract, correlating with theabsolute absorption areas of the different parts of the intestinaltract. They found a relatively high absorption of Carvedilol in thelarge intestine, amounting to approximately 10% of the total absorption.

[0277] This supports the findings from the pilot studies performed onthe Carvedilol Egalet®, where the plasma curves show that Carvedilol isbeing absorbed throughout the GI tract, including the colon, and thatthe absorption in the colon is present, but considerably reducedcompared to earlier in the GI tract. b.

[0278] Fluctuations

[0279] To evaluate fluctuations in plasma concentration, comparisonshould be made between plasma profiles from the same concentrationgiven. Data from pilot study IV and V on Carvedilol IR 50 mg compared toCarvedilol Egalet® 50 mg shows that Cmax for the Carvedilol Egalet® isreduced approximately 50%, whereas the C24h, which will correspond toCmin in a once daily dosing, is 2,5 times as high.

[0280] In the studies, the Carvedilol IR has been given in a singledose. Patients will be taking Carvedilol IR b.i.d., whereforepeak/trough ratio should be measured for this dose regimen. This will bedone in the steady state studies.

[0281] c. Variability

[0282] In published literature the variability of Carvedilol is veryhigh, with standard deviations of >50%. The study with the highestnumber of subjects, i.e. 44 shows a SD of 70%.

[0283] There are no indications that the variability will be higher thanfor the immediate release formulation.

[0284] d. Dose proportionality:

[0285] At this point it is only planned to market one dose of CarvedilolEgalet®, and no investigations into dose proportionality are planned.Literature describes dose linearity for Carvedilol in the range of6,25-50 mg.

[0286] e. Dose dumping:

[0287] Carvedilol is being released from the Egalet tablet by theerosion of the matrix from the exposed surfaces only as the coatprevents contact to the aqueous medium of the intestines. Accordingly,release of all of the Carvedilol at one time is not possible.

[0288] A further advantage of the injection moulding of shell and matrixin one process step is that the shell and the matrix reach a high degreeof adherence.

[0289] An uncoated and thus unprotected matrix has been investigatedthrough dissolution tests, which show that release time in-vitro for afreely exposed Carvedilol matrix from a 9 mm Egalet® is about two hours.Accordingly, the coating actively prevents release due to the limitedexposed area.

[0290] In addition, the in-vivo-in-vitro correlation of the Egalet® hasbeen described to some extend through scintigraphy. 2 hours in vitrorelease in the stomach will correspond to at least 3 hours in vivo, andwill not be below 2 hours. Thus any dose dumping would be of lessseverity than seen after intake of 50 mg conventional immediate releasetablet.

[0291] The immediate release tablet has been investigated as 50 mg o.d.in several clinical studies, but is associated to an increased number ofadverse events, compared to lower doses, due to the increasedtrough-peak ratio.

[0292] f. GI function:

[0293] GI transit time may influence the release rate. A very fasttransit time where the tablet is excreted before the content is fullyreleased, will result in a decreased AUC. This is a well-described issuefor slow release products.

[0294] For the Carvedilol Egalet® the effect of GI transit time can beclearly demonstrated because the non-degradable shell can be collected.When all Carvedilol is released with normal transit times, remainingCarvedilol can be found in the shells with decreased transit time. Thishas been documented in findings from pilot study III.

[0295] As release rate is constant for any given formulation, releasetime is depending on the length of the Egalet® tablet. For the matrixformulation, which releases at the rate of 1 mm/hour in in-vitrodissolution, tablets of 9 mm have shown complete release with normaltransit time.

[0296] The absorption of Carvedilol Egalet® in patients with MorbusCrohn and Collitis ulcerosa has not been investigated. Until that isperformed, the use of the product in the patient population iscontraindicated.

[0297] The effect of food will be evaluated in a traditional PK study.Preliminary information on food effect will be obtained in a pilot studyon 10 volunteers.

[0298] 9. Diumal rhythms

[0299] Carvedilol has been shown to preserve the diurnal rhythm of bloodpressure; there are no reasons to believe that a slow releaseformulation will influence this rhythm differently than the IRformulation. This will be explored in the phase II study, whereambulatory BP will be measured for 24 hours.

[0300] 3. Stereoisomers

[0301] Carvedilol is a racemic mixture of R(+) and S(−)-enantiomers:S(−), which is a potent β1 and β2 antagonist and a-adrenoceptorantagonist and R(+), which has 1/100 of the beta effect and the same aeffect as the S(−). The pharmacokinetics of these is described both inhealthy volunteers and in patients with cardiac insufficiency.

[0302] Theoretically, the plasma profiles of the enantiomers seen afterintake of the Carvedilol Egalet® could be different from the one seenafter Carvedilol immediate release, given that the t½ of the two aredifferent (9.6 h for R(+) and 22.1 h for S(−)). In steady state,however, the plasma profiles are similar to that of Carvedilol, and itis not expected that the blood pressure lowering effect will bedifferent for the Carvedilol Egalet® than for the Carvedilol IR.

Pharmacokinetics

[0303] The development of Carvedilol Egalet® has involvedinvestigational pilot studies on healthy volunteers. No full-scalestudies have been performed up to now.

[0304] Different formulations of Carvedilol Egalet® have been tested andthrough this work the final formulation has been identified, and astrategy was planned for the clinical testing programme.

Pilot Phase I Studies Completed Pharmacokinetic Studies

[0305] The pharnacokinetic studies on Carvedilol Egalet® listed in Table1 are part of the development work to obtain preliminary information onthe pharmacokinetics. TABLE 1 Completed pilot pharmacokinetic studies,listed chronologically Study Doses No. of No. Design Treatment (mg)^(a)subjects Pilot test Single-dose PK: Single-dose C Egalet: 6 IOpen-label, 2-armed, parallel 25 mg group C IR: 25 mg (CarvedilolEgalet ® vs. Carvedilol IR) Pilot test Single-dose PK: Single-dose CEgalet: 6 II Open-label, 2-armed, parallel 50 mg group C IR: 50 mg(Carvedilol Egalet ® vs. Carvedilol IR) Pre-Pilot Single-dose PK:Single-dose C Egalet: 2 I Open-label, Carvedilol Egalet ® 50 mgPre-Pilot Single-dose PK: Single-dose C Egalet: 2 II Open-label,Carvedilol Egalet ® 50 mg Pre-Pilot Single-dose PK: Single-dose CEgalet: 2 III Open-label, Carvedilol Egalet ® 37.5 mg Pre-PilotSingle-dose: Single-dose C Egalet: 2 IV Collection of excreted shells 50mg Pilot test Single-dose PK: Single-dose C Egalet: 6 III Open-label,4-way cross-over study 25 mg/ (3 doses Carvedilol Egalet ® vs. 37.5 mg/Carvedilol IR) 50 mg o.d. C IR: 37.5 mg b.i.d. Pilot Test Single-dosePK: Single-dose C Egalet: 10 IV Open-label, 4-way cross-over 50 mg o.d.(3 different shapes of Carvedilol C IR: 50 mg Egalet ® vs. CarvedilolIR) o.d. Pilot Test Single-dose PK: Single-dose C Egalet: 10 VOpen-label, 4-way cross-over 50 mg o.d. (2 different shapes ofCarvedilol C IR: 50 mg Egalet ® vs. Carvedilol IR) o.d. As a final fixedsequence arm; the chosen shape of Carvedilol Egalet ® in fed subjects

[0306] In all studies, the investigational products were administeredorally as tablets.

[0307] The formulations tested in these studies showed a prolongedrelease of Carvedilol with reduced C_(max) and measurable plasmaconcentrations over 36 hours.

Results and Discussion—Pilot Pharmacokinetic Studies

[0308] The pilot phase I studies completed up to now clearly indicatesthat it is possible to produce a slow release Carvedilol Egalet® with aPK profile required of a once daily formulation.

[0309] In pilot test III, the influence of the length of the Egalet®tablet on the release characteristics was described. In pilot test IV,Egalet® tablets with 3 different diameters and lengths has been tested.In vitro dissolution tests indicated that an increased diameter wouldnot influence the speed of erosion and pilot IV and V has confirmedthis. C_(max) is increasing proportionally to the increasing surfacearea exposed of the Egalet. Tmax does not differ between theformulations. The mean of the plasma concentrations measured for the 6mm Carvedilol Egalet 50 mg is reduced due to an unexpected high numberof subjects having a fast transit time in that treatment group; 6 of 10subjects excreted the Egalet before hour 24.

[0310] In pilot study V, two of the same lengths of Carvedilol Egalet®as in pilot test IV were tested, but in a different oval shape, andcompared to Carvedilol immediate release. Preliminary data assessmentsupports the conclusion from pilot study IV that Cmax increases withincreasing diameter of the Egalet®. When comparing data for the roundEgalet in pilot IV to the “easy-to-swallow” oval shaped Egalet in pilotV, for the 6 mm and the 7½ mm lengths respectively, and the exposedmatrix area being constant, there are no observed difference by thechange of shape. To obtain preliminary information on the effect of foodon Carvedilol Egalet®, the 6 mm Egalet formulation was tested after astandard, high-fat meal, according to guidelines. The first 3 arms ofthe study were randomised and the last, the fed, was a fixed sequencearm. The data results from the last sequence have not been received yetand full data analysis for pilot study V has thus not been completed.

[0311] The composition, the Carvedilol Egalet® 6 mm, is a composition,for which we aim at showing an AUC equivalent to the marketedtwice-daily formulation. Preliminary data assessment from pilot study Vshows for the 6 mm oval Egalet an AUC of 97,7% of the AUC C C C t (0-36h) rel. max (12 h) (24 h) max Formulation n h*ng/ml AUC % ng/ml ng/mlng/ml hours CL-EG-01 (round egalet) 9 mm 10 285 70 26.7 7.1 4.2 3 7½ mm10 355 88 37.8 10.3 3.8 4 6 mm 10 336 76 37.4 9.1 2.9 4 IR 10 433 100105.5 5.8 1.9 1 CL-EG-02 (oval egalet) IR 10 444 100 95.8 6.6 2.4 1 7½mm 10 344 76 33.2 9.0 5.0 4 6 mm 10 421 97 41.7 11.8 4.8 4 6 mm + food10 362 80 39.0 10.9 3.9 3

[0312] In the table is given relevant pharmacokinetic parameters fromthe pilot studies (see FIG. 1).

Example 6 Preparation of a Morphine Containing Controlled ReleaseComposition According to the Invention

[0313] A composition (batch No. 01-0112-066) according to the inventionwas prepared from the following ingredients: Matrix Polyethylene oxide200,000 83.5% w//w Morphine sulfate 16.5% w/w

[0314] The coating and the matrix were prepared as described above. Thecomposition was 9 mm long and had elliptic formed surfaces.

[0315] The composition was subjected to the dissolution test describedabove. The following results were obtained: % w/w release morphine Time(hours) sulfate from the composition 1 19.48 2 33.64 3 44.22 4 55.59 570.11 6 80.70 7 91.30 8 96.65

[0316] The release corresponds to a zero order release.

Example 7 Preparation of a Composition of Carvedilol—DSC Measurements

[0317] A composition according to the invention was made from thefollowing: PEO 200,000 67% w/w Carvedilol 28% w/w Citric acid  5% w/w

[0318] The composition was made according to the general processdescribed herein.

[0319] All starting materials as well as a mixture of PEO 200,000 andcitric acid was subject to differential scanning caliometry measurements(thermal measurement). The final composition was also investigated attime 0 and 1 month after storage at 25° C./60% RH and 40° C./70% RH. Theresults are shown in FIGS. 3-7.

Example 8 Composition According to the Invention

[0320] The example illustrates the invention and gives a number ofdifferent compositions according to the invention. In the right handcolumn is given comments to the individual compositions with respect tothe impact on the composition of the ingredients employed and withrespect to the dissolution profile obtained.

[0321] Abbreviations: PEG: polyethylene glycol PEG ms: polyethyleneglycol monostearat HPMCP HP 50: hydroxypropyl methylcellulose pthalate(HP 50 is grade) TPGS: α-tocopheryl polyethylene glycol succinateDesired Release time Matrix % 12 hours in 12 mm long Ingredient w/wtubular tablet. Result Polymer system EC-042-011 PEO 200 000 86 Nozero-order release in acid 25 mg Carvedilol Carvedilol 14 medium,release time after 17 h. EC-042-013 PEO 200 000 50 No zero-orderrelease, 25 mg Carvedilol Carvedilol 14 release time after 14 h. Lactose24 Klucel 5 PEG 2000 ms 7 EC-042-014 PEO 200 000 81 Released after 14 h.After 1 25 mg Carvedilol Carvedilol 14 month (18-22° C.), no PEG 2000 ms5 release in buffer. EC-042-015 PEO 200 000 81 Release time after more25 mg Carvedilol Carvedilol 14 than 20 h. Matrix left in HPMCP HP 50 5the shell. EC-042-016 PEO 200 000 76 Release time after 16 h. 25 mgCarvedilol Carvedilol 14 Matrix left in the shell. PEG 2000 ms 5 HPMCPHP 50 5 EC-042-020 PEO 200 000 81 Released after 12 h. Almost 25 mgCarvedilol Carvedilol 14 zero-order. PEG 2000 ms 5 EC-042-024 PEO 200000 70 Released after 11 h. After 2-3 25 mg Carvedilol Carvedilol 14month storage (18° C.-22° C.), PEG 2000 ms 16 no release in buffer.EC-042-025 PEO 200 000 65 Release time increased but 25 mg CarvedilolCarvedilol 14 HPMCP did not lower the PEG 2000 ms 14 release rate inacid medium. Hydroxyethyl cellulose 4 Release time after 15 h.(Natrosol) 3 No zero-order release. HPMCP HP 50 EC-042-030 PEO 200 00052 No zero order release. 50 mg Carvedilol Carvedilol 32 PEG 2000 ms 16EC-042-031 PEO 600 000 52 No zero order release. 50 mg CarvedilolCarvedilol 32 PEG 2000 ms 16 EC-042-034 PEO 45.000 70 No zero-orderrelease, the 25 mg Carvedilol PEG 2000 ms 14 matrix swell. Carvedilol 16EC-042-037 PEO 200.000 52 No zero-order release. 50 mg CarvedilolCarvedilol 32 Release time 14-16 h. PEG 2000 ms 16 Carvedilolprecipitated in buffer medium. EC-042-039 PEO 200.000 52 No zero orderrelease, 50 mg Carvedilol Carvedilol 32 release time > 25 h. PEG 2000 ms6 Starch increased the release Starch 10 time EC-042-042 PEO 200.000 43Too low release rate, 50 mg Carvedilol Carvedilol 32 Carbomer 974dereased the PEG 2000 ms 10 release time Carbomer 974 15 EC-042-043 PEO200.000 47 Too low release rate, 50 mg Carvedilol Carvedilol 32 Carbomer974 dereased the PEG 2000 ms 16 release time Carbomer 974 5 EC-042-044PEO 200.000 55 Too low release. 50 mg Carvedilol Carvedilol 32 Carbomerdecreased the PEG 2000 ms 10 release. Carbomer 974 3 EC-042-048 PEO200.000 68 No release in buffer medium. 50 mg Carvedilol Carvedilol 32Precipitation of carvedilol EC-042-051 PEO 200.000 68 No release inbuffer medium. 50 mg Carvedilol Carvedilol 32 Precipitation ofcarvedilol EC-042-052 PEO 200.000 84 Almost zero-order release. 25 mgCarvedilol Carvedilol 16 Release time 15 h. Formulation was unstable.Acidic stabilizicers EC-042-045 PEO 200.000 47 Release time was tooshort. 50 mg Carvedilol PEG 2000 ms 16 Zero-order release, releaseCarvedilol 32 time 11 h Faster release in Citric Acid 5 acid than inbuffer EC-042-050 PEO 200.000 47 Zero-order, release time too 50 mgCarvedilol PEG 2000 ms 16 short. Faster release in acid Carvedilol 32than in buffer Succinic Acid 5 EC-042-066 PEO 200.000 58 Zero-order, 50mg Carvedilol PEG 2000 ms 5 release time 12 h. Faster Carvedilol 32release in acid than in buffer Citric Acid 5 EC-042-069 PEO 200.000 40No zero-order release. 50 mg Carvedilol Carvedilol 32 Release in acidmedium faster PEG 2000 ms 3 than in buffer. Some matrix Pectin 20 wasstill left in the matrix. Citric Acid 5 Pectin delayed releaseEC-042-070 PEO 200.000 40 No release in buffer 50 mg CarvedilolCarvedilol 32 medium. PEG 2000 ms 3 Starch (com) 20 Citric Acid 5EC-042-081 PEG 35.000 42 Zero-order release, release 50 mg CarvedilolPEO 600.000 21 time 16 h. Matrix was left in Carvedilol 32 the shell.PEO 600.000 Citric Acid 5 delayed the release EC-042-082 PEG 35.000 39No zero-order release. 50 mg Carvedilol PEO 600.000 19 Release time > 18h. Carvedilol 32 PEG 2000 ms 5 Citric Acid 5 EC-042-083 PEO 600.000 10Zero-order release. Release 50 mg Carvedilol PEO 200.000 69 time > 18 h.Carvedilol 16 Matrix left in the shell. Citric Acid 5 PEO 600.000delayed the release. Matrix % Ingredient w/w Conclusion EC-042-047 PEO200.000 63 Zero-order, release time 50 mg Carvedilol Carvedilol 32 14 h.Citric Acid 5 EC-042-049 PEO 200.000 63 Succinic acid could be used 50mg Carvedilol Carvedilol 32 instead of citric acid as Succinic Acid 5release time and release pattern were the same. EC-042-053 PEO 200.00065.5 Amount of citric acid too 50 mg Carvedilol Carvedilol 32 small.Same slope in acid Citric Acid 2.5 and buffer was not observed.EC-042-054 PEO 200.000 58 Amount of citric acid too 50 mg CarvedilolCarvedilol 32 high. Same slope in acid and Citric Acid 10 buffer was notobserved. EC-042-073 PEO 200.000 61 Almost zero-order release. 50 mgCarvedilol Carvedilol 32 Release in acid faster than in Citric Acid 5buffer. Matrix left in the shell. Tristearin 2 EC-042-077 PEO 200.00081.5 Zero-order release, release 25 mg Carvedilol Carvedilol 16 time 14h. Comparable with Citric Acid 2.5 50 mg carvedilol EC-042-047EC-042-078 PEO 200.000 90.75 Zero-order release, release 12.5 mgCarvedilol Carvedilol 8 time 14 h. Comparable with Citric Acid 1.25 50mg and 25 mg EC-042-047 and EC-042-077 EC-042-079 PEO 200.000 79 Releaseprofile in acid 25 mg Carvedilol Carvedilol 16 medium was increased whenCitric Acid 5 Citric Acid/Carv increased EC-042-080 PEG 35.000 63 PEG35000 increased 50 mg Carvedilol Carvedilol 32 the release in acidCitric Acid 5 medium. Undesired EC-042-084 PEO 200.000 74 Almostzero-order, release 50 mg Carvedilol Carvedilol 16 time 13 h. Aluminiumlactate Citric Acid 5 reduced the release in acid Aluminum lactate 5medium. Addition of Zink Sulphate EC-042-085 PEO 200.000 77.5 Zero-orderrelease, release 25 mg Carvedilol Carvedilol 16 time 14 h. Citric Acid 5Zink Sulphate decreased Zink Sulphate 1.5 release in acid compared tobuffer. EC-042-086 PEO 200.000 74.5 Zero-order release, release 25 mgCarvedilol Carvedilol 16 time 14 h. Citric Acid 5 Zink Sulphatedecreased Zinc Sulphate 4.5 release in acid compared to bufferEC-042-087 PEO 200.000 79.5 Zero-order release, release 25 mg CarvedilolCarvedilol 16 time 13 h. Zink Sulphate Citric Acid 2.5 decreased releasein acid Zinc Sulphate 2 Polymer with inorganic ingredients EC-042-040PEO 200.000 52 No release in buffer medium. 50 mg Carvedilol PEG 2000 ms6 See also EC-042-037, not Carvedilol 32 comprising SiO2 SiO2 10 BatchMatrix % No. Formulation Ingredient w/w Conclusion Polymer 042-130 50 mgCarvedilol PEO 100.000 74.8 The dissolution profile Carvedilol 24 showszero-order release. Potassium Sulfite 0.2 Sucrose 0.5 BHT 0.5 042-149 50mg Carvedilol PEO 200.000 LF 76 The dissolution profile Carvedilol 24shows zero-order release, however different slope between acid andbuffer. Organic antioxidants 042-115 50 mg Carvedilol PEO 200.000 75.9Diminishes degradation Carvedilol 24 of PEO 200.000 and Ascorbic acid0.1 Carvedilol. The dissolution profile shows zero-order release.042-116 50 mg Carvedilol PEO 100.000 75.9 Diminishes degradationCarvedilol 24 of PEO 100.000 and Ascorbic acid 0.1 Carvedilol. Thedissolution profile shows zero-order release. 042-133 50 mg CarvedilolPEO 200.000 72.3 Diminishes degradation Carvedilol 24 of PEO 200.000 andPotassium Sulfite 0.2 Carvedilol. The Salicylic acid 3 dissolutionprofile shows BHT 0.5 zero-order release. 042-135 50 mg Carvedilol PEO200.000 74.7 The increased dosage of Carvedilol 24 BHT did not produceany Potassium significant change in the Metabisulfite 0.2 level ofimpurities caused BHT 1 by PEO 200.000 Gentisic acid 0.1 compred to 0.5%BHT The dissolution profile does not show zero-order release. 042-136 50mg Carvedilol PEO 200.000 74.6 The increased dosage of Carvedilol 24 BHTdid not produce any Potassium significant change in the Metabisulfite0.2 level of impurities caused BHT 1 by PEO 200.000 Gentisic acid 0.2compatred to 0.5% BHT The dissolution profile does not show zero-orderrelease. 042-141 50 mg Carvedilol PEO 200.000 64.765 The increaseddosage of Carvedilol 24 BHT did not produce any Potassium significantchange in the Metabisulfite 0.2 level of impurities caused BHT 1 by PEO200.000 Sorbitol 10 compared to 0.5% BHT HCl 0.035 The dissolutionprofile does not show zero-order release. 2.3 Inorganic antioxidants042-117 50 mg Carvedilol PEO 200.000 75.9 Diminishes degradation ofCarvedilol 24 PEO 200.000 and Potassium Carvedilol. The Metabisulfite0.1 dissolution profile shows zero-order release. 042-133 50 mgCarvedilol PEO 200.000 72.3 Diminishes degradation of Carvedilol 24 PEO200.000 and Potassium Carvedilol. The Metabisulfite 0.2 dissolutionprofile shows Salicylic acid 3 zero-order release. BHT 0.5 042-134 50 mgCarvedilol PEO 200.000 74.8 Diminishes degradation of Carvedilol 24 PEO200.000 and Potassium Carvedilol. The Metabisulfite 0.2 dissolutionprofile shows BHT 1 zero-order release. 6. Sugars 042-118 50 mgCarvedilol PEO 200.000 75.8 The dissolution profile Carvedilol 24 showszero-order release. Potassium Sulfite 0.1 Sucrose 0.1 042-120 50 mgCarvedilol PEO 200.000 70.9 Production cancelled, the Carvedilol 24Concentrasion of Potassium Sulfite 0.1 Sucrose to hight for the Sucrose5.0 selected process parameters. May be produced with increasedtemperature 042-121 50 mg Carvedilol PEO 200.000 65.9 Carvedilolprecipitated Carvedilol 24 when standing. Potassium Sulfite 0.1 Mannitol10 042-122 50 mg Carvedilol PEO 200.000 73.3 Concentration of SucroseCarvedilol 24 to high for the selected Potassium Sulfite 0.2 processparameters. May Sucrose 2 be produced with BHT 0.5 increasedtemperature. 042-123 50 mg Carvedilol PEO 200.000 71.8 The concentrationwas Carvedilol 24 too high and resulted in Potassium Sulfite 0.2 processproblems. Sucrose 3.5 Production cancelled. BHT 0.5 042-129 50 mgCarvedilol PEO 200.000 74.8 The dissolution profile Carvedilol 24 showszero-order Potassium Sulfite 0.2 release. Sucrose 0.5 BHT 0.5 042-130 50mg Carvedilol PEO 100.000 74.8 The dissolution profile Carvedilol 24shows zero-order Potassium Sulfite 0.2 release. Sucrose 0.5 BHT 0.5042-137 50 mg Carvedilol PEO 200.000 59.8 Mannitol did not produceCarvedilol 24 the expected result, Potassium because CarvedilolMetabisulfite 0.2 precipitated when BHT 1 standing. Mannitol 15 042-14150 mg Carvedilol PEO 200.000 64.765 Carvedilol precipitated Carvedilol24 after standing Potassium approximately one week. Metabisulfite 0.2BHT 1 Sorbitol 10 HCl 0.035 Increase in hydrogen bondings 042-128 50 mgCarvedilol PEO 200.000 74.8 Carvedilol precipitated Carvedilol 24 afterstanding Potassium approximately one week. Metabisulfite 0.2 Dissolutionprofile shows 2-amino- zero-order release. 2(hydroxymethyl)1,3 ropandiol0.5 BHT 0.5 042-131 50 mg Carvedilol PEO 200.000 74.3 Dissolutionprofile shows Carvedilol 24 zero-order release. Potassium Metabisulfite0.2 Klucel 1 BHT 0.5 042-142 50 mg Carvedilol PEO 200.000 74 Thedissolution profile is Carvedilol 24 zero-order. PVP K90 2 042-143- 50mg Carvedilol PEO 200.000 71 Dissolution not zero- 02-001 Carvedilol 24order. Sorbitol 5 042-144 50 mg Carvedilol PEO 200.000 73 Dissolutionnot zero- Carvedilol 24 order. Cyclodextrin 3 042-145 50 mg CarvedilolPEO 200.000 69 Dissolution not zero- Carvedilol 24 order. Cyclodextrin 7042-141 50 mg Carvedilol PEO 200.000 64.765 Dissolution profile doesCarvedilol 24 not show zero-order Potassium release, possibly due toMetabisulfite 0.2 the amount of BHT. BHT 1 Sorbitol 10 HCl 0.035 042-14850 mg Carvedilol PEO 200.000 72 The dissolution profile Carvedilol 24.1does not show zero-order Potassium release possibly due to Metabisulfite0.2 the amount of BHT. BHT 1 KH₂PO₄ 0.32 HCl 0.61 PVP K90 1.7 042-153 50mg Carvedilol PEO 200.000 68.5 Test of granulation Carvedilol 24 methodPotassium Metabisulfite 0.2 BHT 0.5 KH₂PO₄ 0.20 H₃PO₄ 4.6 PVP K90 2.0

[0322] Examples disclosing Formulation Nos 68 to 84.

[0323] 6 mm oval shaped formulations 150 mm² 0068 Dry mixing with solidphosphoric acid. PEO 200.000, pH 7.27 Carv.(24.0%), Base lineDissolution zero-order, erosion time 7 hours, not PM (0.2%), completedissolution at hour 8, matrix on bottom of vessel BHT(0.5%);Meta-Phosphoric acid* Carv/acid*: 4.6 (5.2%); Carv/HPO3: 10.9) PVP K90(2.0%) 0069 Dry mixing: Acid(s) and PEO mixed in mortar. Blended and PEO200.000 81.7% crushed. All mixed. Mix kept dry. Carv.(12.0%), pH 7.27 PM(0.2%), Appearance of tablets after production: BHT(0.5%); Transparentyellowish Meta-Phosphoric acid* Baseline Dissolution, zero-order,erosion time 6.5 hours, (3.6%) complete dissolution at hour 7 PVP K90(2.0%) Dissolution in simulated fasted and fed media zero-order (FIGS. 8and 9) Carv/acid*: 3.3 Carv/HPO3: 7.9) Appearance/Dissolution after 26days storage at 30° C./60% Rh: Transparent yellowish/Zero-order erosiontime 6 hours, complete dissolution after 6.5 hours (FIG. 10) Notproduced Carvedilol/acid ratio 3.3* (7.9 based on HO3P) PEO 200.000LF83.7% Exptected values: Carv.(12.0%), pH about 6 PM (0.2%), Appearanceof tablets transparent yellowish BHT(0.5%); Dissolution, zero-orderMeta-Phosphoric acid* (3.6%)(42.1% HO3P) 0070 Dry mixing: H3PO4(s) inPEO. Then mixed with rest. Mix PEO 200.000, kept dry. Carv.(24.0%), pH5.93 PM (0.2%), Appearance after production: White BHT(0.5%); BaselineDissolution: Carvedilol.not released in buffer due Ortho-Phosphoric acidto crystallization. (4.4%); Carvedilol/acid**: 5.45 PVP K90 (2.0%)Composition Dry mixing: H3PO4(s) in PEO. Then mixed with rest. Mix 0073kept dry. PEO 200.000 (LF), pH 3.23 Carv. (18.0%), Appearance afterproduction: Transparent yellowish, PM (0.2%), Dissolution: BHT(0.5%);Dissolution, zero-order, erosion time 6 hours, complete Ortho-Phosphoricacid dissolution at hour 6.5 (4.5%); Carv/acid**: 4 PVP K90 (2.0%)Appearance: After 1-2 weeks storage white 0075 PEO 200.000(LF) Drymixing: H3PO4(s) in 40 g PEO. Rest of PEO mixed Carv. (18.0%), withcarv. + antioxidants. Mixed all. Mix kept dry. PM (0.2%), pH 5.71BHT(0.5%); Appearance after production: White Ortho-Phosphoric acidDissolution: Cancelled due to crystallization (3.6%); Carv/acid**: 5 PVPK90 (2.0%) 0083 Dry mixing: Powders mixed and H3PO4 (I) mixed in somePEO 200.000(LF), of the powders. All mixed. Mix kept dry. pH in mixture3.84 Carv. (12.0%), Appearance after production: White PM (0.2%),Dissolution: Cancelled due to crystallization BHT(0.5%); Carv/acid**: 5Ortho-Phosphoric acid (2.4%); PVP K90 (2.0%) 0084 pH 3.23 (mixture) PEO200.000 (LF), Appearance after production: Transparent yellowish, Carv.(12.0%), Dissolution: Zero-order, erosion time 6 hours, complete PM(0.2%), dissolution at hour 6.5 BHT(0.5%); Meta-Phosphoric acid*Carv/acid*: 3.3 (3.6%); Carv/HPO3: 7.9) PVP K90 (2.0%)

A General Method for the Preparation of a Controlled Release Compositionis Described Below for the Following Examples Preparation of the MatrixComposition

[0324] An accurate amount of the polymer (i.e. in the examples below:the polyethylene oxide) is loaded into a MTI mixer followed by anaccurate amount of the active substance and of the pharmaceuticallyacceptable excipients(s), if any. The mixing is performed at 2000/1500rpm and at a time period of from 10 min to 20 min. At the start of themixing the temperature is about 19° C. and the final temperature of themixture is about 40-43° C. The mixture is then allowed to cool to roomtemperature and is ready to be fed into an injection moulding machine.

[0325] When TPGS is included in the composition, TPGS and PEO arepremixed by adding melted TPGS to PEO followed by mixing.

Example 9 Preparation of a Morphine Containing Controlled ReleaseComposition According to the Invention

[0326] A composition (batch No. 01-0112-066) according to the inventionwas prepared from the following ingredients: Matrix Polyethylene oxide200,000 83.5% w//w Morphine sulfate 16.5% w/w

[0327] The coating and the matrix were prepared as described above. Thecomposition was 9 mm long and had elliptic formed surfaces.

[0328] The composition was subjected to the dissolution test describedabove. The following results were obtained: % w/w release morphine Time(hours) sulfate from the composition 9 19.48 10 33.64 11 44.22 12 55.5913 70.11 14 80.70 15 91.30 16 96.65

[0329] The result is also shown in FIG. 12 and the release correspondsto a zero order release.

Example 10 Preparation of Morphine-containing Compositions According tothe Invention

[0330] In the table below is given details on the composition of 4different morphine compositions. The content of morphine sulphate in allcompositions corresponds to 30 mg morphine sulphate. The volumes of thedifferent compositions were the same, whereas the diameter of the openend surfaces varies. Composition (% w/w) PEO Morphine AlO₂, No.Length/mm 200.000 Sulphate TPGS 3H₂O Mannitol 1B 7.5; Ellipse^(a) 76.518.7 2.5 2.3 2B 12; round^(b) 68.7 18.7 2.6 10.0 2A 9; round^(c) 69.917.5 2.6 10.0 1A 9; round^(d) 77.3 17.9 2.5 2.4

[0331] All compositions demonstrated 6 months accelerated stability at40° C./75% RH and 12 months stability at 25° C./75% RH. In allcompositions each single impurity is below 0.1% w/w.

[0332] In the following is given the data for the dissolution profilesof each composition:

[0333] Composition 2A (see FIG. 13-2A): % active substance Time/hdissolved 0.0 −0.36 1.0 23.45 20.0 2.0 41.3 35.2 3.0 59.5 50.7 4.0 75.9364.7 5.0 90.83 77.4 6.0 107.34 91.5 6.5 113.26 96.6 7.0 116.67 99.4 7.5117.24 100 8.0 117.28 100

[0334] Composition 2B (see FIG. 14-2B) % active substance Time/hdissolved 0.0 −0.48 1.0 19.22 16.9 2.0 34.44 30.0 3.0 44.3 39.0 4.055.52 48.8 5.0 66.13 58.2 6.0 76.93 67.7 7.0 87.19 76.7 8.0 98.11 86.39.0 109.04 96.0 9.5 111.26 97.8 10.0 112.63 99.1 10.5 113.48 100 11.0113.66 100

[0335] Composition 1B (see FIG. 13-1B) % active substance Time/hdissolved 0.0 −0.47 1.0 30.15 23.7 2.0 55.72 43.9 3.0 77.54 61.1 4.097.55 76.8 5.0 117.57 92.6 5.5 124.77 98.2 6.0 126.89 100 6.5 126.93 100

[0336] Composition 1A (see FIG. 13-1A) % active substance Time/hdissolved 0.0 −0.423 1.0 23.17 19.3 2.0 40.47 33.8 3.0 53.27 44.4 4.067.13 56.0 5.0 80.67 67.3 6.0 101.23 84.4 7.0 108.16 90.2 7.5 114.5395.6 8.0 119.78 100

[0337] The results show that the use of mannitol or aluminiumoxide as aDDA leads to the desired zero order release of morphine sulphate from acomposition according to the invention. The above-mentioned compositionswere subject to a clinical study. The clinical study is reported in thefollowing example.

Example 11 A Single Dose, Randomized, Cross-over, Pharmacokinetic PilotStudy on Four Different Morphine Compositions According to the Invention

[0338] The objectives were to study the pharmacokinetics of morphineafter administration of four different morphine compositions accordingto the invention. The compositions had different shape and size and theDDAs employed in order to enable a zero order dissolution profile weredifferent (mannitol and aluminium oxide, respectively).

[0339] 16 healthy male volunteers aged 20 to 40 who had given theirwritten informed consent were included in the study.

[0340] The volunteers were screened up to three weeks prior to baseline.The first treatment was administered at the baseline visit and secondtreatment was administered after 2 weeks of wash out. Follow-up visitstook place 30 days after the second study period.

[0341] The compositions tested were those described in Example 2 above.The dose given corresponds to 30 mg morphine sulphate.

[0342] The results of the study are shown in FIG. 14. In FIG. 14 is alsoincluded data for a comparitive composition, Dolcontin. The resultsindicate that the shape as well as the size of the composition areimportant.

[0343] Another clinical study has also been performed as a phase II,open, prospective, controlled study in patients with chronic pain. Thestudy included 13 patients with chronic pain for any reason judged bythe investigator as stable and in need of opioids analgesics. Acomposition according to the invention was tested and compared with acommercially available morphine containing composition, Dolcontin. Thetotal morphine sulphate released from the composition according to theinvention was about 20 mg (the dosage in Dolcontin was 30 mg). Althoughthere was a difference in the amount administered, it was evident fromthe study that the therapeutic effect of a composition according to theinvention was not different from Dolcontin, i.e. a reduction is theoverall dose may be reduced by the use a zero order release composition.Moreover, the adverse effects reported were less compared to theDolcontin composition, most likely due to the smaller amount of morphinesulphate administered. Another interesting feature is that during thestudy rescue medication was allowed and there was no difference in theintake of rescue medicine of patients administered with Dolcontin orwith a composition according to the invention. FIG. 15 shows the plasmaconcentration versus time profiles from the study.

1. A method for controlling the release of at least one therapeutically,prophylactically and/or diagnostically active substance into an aqueousmedium by erosion of at least one surface of a pharmaceuticalcomposition comprising i) a matrix composition comprising a) asubstantially water soluble or crystalline polymer or a mixture ofsubstantially water soluble and/or crystalline polymers, b) an activesubstance and, optionally, c) one or more pharmaceutically acceptableexcipients, and ii) a coating having at least one opening exposing atthe one surface of said matrix, the coating comprising a) a firstcellulose derivative which has thermoplastic properties and which issubstantially insoluble in the aqueous medium in which the compositionis to be used and at least one of b) a second cellulose derivative whichis soluble or dispersible in water, c) a plasticizer, and d) a filler,and wherein the diffusion rate of the aqueous medium into the matrixcomposition corresponds to about 100%±30% such as, e.g. about 100%±25%,about 100%±20%, about 100%±15% or about 100%±10% or about 100% of thedissolution rate of the matrix composition, and wherein any matrixsurface exposed to the aqueous medium erodes so as to obtain a zeroorder release of at least about 60% w/w such as, e.g. at least about 65%w/w at least about 70% w/w, at least about 75% w/w, at least about 80%w/w, at least about 85% w/w, at least about 90% w/w, at least about 95%w/w or at least about 97 or 98% w/w of the active substance from thepharmaceutical composition when subject to an in vitro dissolution testas described herein.
 2. A method according to claim 1, wherein thepolymer is a substantially water soluble or crystalline polymer or amixture of substantially water soluble and/or crystalline polymers.
 3. Amethod according to claim 1, wherein the matrix comprises apharmaceutically acceptable excipient functioning as a diffusion anddissolution adjusting agent.
 4. A method according to claim 1, whereinthe pharmaceutically acceptable excipient is selected from the groupconsisting of inorganic acids, inorganic bases, inorganic salts, organicacids or bases and pharmaceutically acceptable salts thereof,saccharides, oligosaccharides, polysaccharides, and cellulose andcellulose derivatives.
 5. A method according to claim 4, wherein theorganic acid is a mono-, di-, oligo, polycarboxylic acid or an aminoacid selected from the group consisting of acetic acid, ethanoic acid,succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid,malic acid, maleic acid, adipic acid, angelic acid, ascorbicacid/vitamin C, carbamic acid, cinnamic acid, citramalic acid, formicacid, fumaric acid, gallic acid, gentisic acid, glutaconic acid,glutaric acid, glyceric acid, glycolic acid, glyoxylic acid, lacticacid, levulinic acid, malonic acid, mandelic acid, oxalic acid, oxamicacid, pimelic acid pyruvic acid, aspartic acid , and glutamic acid.
 6. Amethod according to claim 4, wherein the inorganic acid is selected fromthe group consisting of pyrophosphoric, glycerophosphoric, phosphoricsuch as ortho or meta phosphoric, boric acid, hydrochloric acid, andsulfuric acid.
 7. A method according to claim 4, wherein the suitableinorganic compounds include aluminium.
 8. A method according to claim 4,wherein the suitable organic bases are selected from the groupconsisting of p-nitrophenol, succinimide, benzenesulfonamide,2-hydroxy-2cyclohexenone, imidazole, pyrrole, diethanolamine,ethyleneamine,tris (hydroxymethyl) aminomethane, hydroxylamine andderivates of amines, sodium citrate, aniline, and hydrazine.
 9. A methodaccording to claim 4, wherein the suitable inorganic bases are selectedfrom the group consisting of aluminium oxide such as, e.g., aluminiumoxide trihydrate, alumina, sodium hydroxide, potassium hydroxide,calcium carbonate, ammonium carbonate, ammnonium hydroxide, KOH and thelike.
 10. A method according to claim 4, wherein the pharmaceuticallyacceptable salt of an organic acid is e.g. an alkali metal salt or analkaline earth metal salt selected from the group consisting of sodiumphosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate,potassium phosphate, potassium dihydrogenphosphate, potassiumhydrogenphosphate, calcium phosphate, dicalcium phosphate, sodiumsulfate, potassium sulfate, calcium sulfate, sodium carbonate, sodiumhydrogencarbonate, potassium carbonate, potassium hydrogencarbonate,calcium carbonate, magnesium carbonate, sodium acetate, potassiumacetate, calcium acetate, sodium succinate, potassium succinate, calciumsuccinate, sodium citrate, potassium citrate, calcium citrate, sodiumtartrate, potassium tartrate, calcium tartrate, zinc gluconate, and zincsulphate.
 11. A method according to claim 4, wherein the inorganic saltis sodium chloride, potassium chloride, calcium chloride, or magnesiumchloride etc.
 12. A method according to claim 4, wherein thepharmaceutically acceptable excipient is selected from the groupconsisting of glucose and other monosaccharides, ribose, arabinose,xylose, lyxose, allose, altrose, inosito, glucose, sorbitol, mannose,gulose, idose, galactose, talose, mannitol, fructose, lactose, sucrose,and other disaccharides, dextrin, dextran or other polysaccharides,amylose, xylan, cellulose and cellulose derivatives such as, e.g.microcrystalline cellulose, methyl cellulose, ethyl cellulose,ethylhydroxyethyl cellulose, ethylmethylcellulose,hydroxyethylcellulose, hydroxyethylmethyl cellulose, carboxymethylcellulose, hydroxypropyl cellulose, hydroxymethylpropyl cellulose,hydroxypropylmethyl cellulose, amylopectin, pectin, starch, sodiumstarch etc., kaolin, bentonit, acacia, alginic acid, sodium alginate,calcium alginate, gelatin, dextrose, molasses, extract of Irish moss,panwar gum, ghatti gum, mucilage of isapol husk, veegum, glycollate,magnesium stearate, calcium stearate, stearic acid, talc, titaniumdioxide, silicium dioxide, clays, croscarmellose, gums, and agar.
 13. Amethod according to claim 1 further comprising a pharmaceuticallyacceptable excipient selected from the group consisting of fillers,diluents, disintegrants, glidants, pH-adjusting agents, viscosityadjusting agents, solubility increasing or decreasing agents,osmotically active agents and solvents.
 14. A method according to claim1, wherein the polymer matrix comprises a polyglycol.
 15. A methodaccording to claim 1, wherein the matrix comprises a homopolymer and/ora copolymer.
 16. A method according claim 1, wherein the matrixcomprises a polyethylene glycol, a polyethylene oxide and/or a blockcopolymer of ethylene oxide and propylene oxide including includingpoly(ethylene-glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethyleneglycol (PEG-PLGA PEG), poly((DL-lactic acid-co-glycolic acid)-g-ethyleneglycol) (PLGA-g-PEG), and polyethylene oxide-polypropylene oxide(PEO-PPO).
 17. A method according to claim 16, wherein the polyethyleneglycol, a polyethylene oxide and/or a block copolymer of ethylene oxideand propylene oxide has a molecular weight of from about 20,000 daltons,such as, e.g., from about 20,000 to about 700,000 daltons, from about20,000 to about 600,000 daltons, from about 35,000 to about 500,000daltons, from about 35,000 to about 400,000 daltons, from about 35,000to about 300,000 daltons, from about 50,000 to about 300,000 daltons,such as, e.g. about 35,000 daltons, about 50,000 daltons, about 75,000daltons, about 100,000 daltons, about 150,000 daltons, about 200,000daltons, about 250,000 daltons, about 300,000 daltons or about 400,000daltons.
 18. A method according to claim 16, wherein the block copolymerof ethylene oxide and propylene oxide comprises up to about 30% w/w ofthe propylene oxide based block, and has a molecular weight of about5,000 daltons, typically about 5,000 to about 30,000 daltons such as,e.g. from about 8,000 to about 15,000 daltons.
 19. A method according toclaim 1, wherein the matrix comprises a polymer which has a meltingpoint of about 20-120° C. such as, e.g. from about 30 to about 100° C.or from about 40 to about 80° C.
 20. A method according to claim 1,wherein the active substance is present in the matrix composition in aconcentration of from about 0.1 to about 98% w/w such as, e.g. at themost about 90% w/w, at the most about 85% w/w, at the most about 80%w/w, at the most about 75% w/w, at the most about 70% w/w, at the mostabout 65% w/w or at the most about 60% w/w.
 21. A method according toclaim 1, wherein the active substance is a substance for human orveterinary use, a vitamin or other nutritional supplement, adisinfectant, a deodorant or another substance to be administeredcontinuously in an aqueous environment.
 22. A method according to claim1, wherein the active substance is present in the matrix at least partlyon amorphous form.
 23. A method according to claim 1, wherein the activesubstance is a pharmaceutically active powder.
 24. A method according toclaim 23, wherein the powder has a particle size of from about 0.1 μm toabout 500 μm, typically from about 0.5 μm to about 300 μm, moretypically from about 1 μm to about 200 μm, especially from about 5 μm toabout 100 μm.
 25. A method according to claim 1, wherein the at leastone therapeutically, prophylactically and/or diagnostically activesubstance has a solubility of at the most about 3 mg/ml such as, e.g. atthe most about 1 mg/ml, at the most about 0.1 mg/ml, at the most about0.05 mg/ml such as, e.g. at the most about 0.001 mg/ml in water atambient temperature.
 26. A method according to claim 25, wherein thematrix composition comprises a pharmaceutically acceptable excipientwhich has a solubility of at least 1 mg/ml such as, e.g. at least about3 mg/ml, at least about 5 mg/ml, at least about 10 mg/ml, at least about25 mg/ml or at least about 50 mg/ml in water at ambient temperature. 27.A method according to claim 1, wherein the at least one therapeutically,prophylactically and/or diagnostically active substance has a solubilityof at least about 3 mg/ml such as, e.g., at least about 5 mg/ml, atleast about 10 mg/ml, at least about 20 mg/ml, at least about 50 mg/mlor at least about 100 mg/ml in water at ambient temperature.
 28. Amethod according to claim 27, wherein the matrix composition comprises apharmaceutically acceptable excipient, which has a solubility of at themost about 3 mg/ml such as, e.g., at the most about 1 mg/ml, at the mostabout 0.1 mg/ml, at the most about 0.05 mg/ml such as, e.g. at the mostabout 0.001 mg/ml in water at ambient temperature.
 29. (Cancelled). 30.A method according to claim 1, wherein in the aqueous medium in whichthe composition is to be used, the coating does not completely crumbleor erode before the matrix has completely eroded.
 31. A method accordingclaim 1, wherein said first cellulose derivative is a cellulose etherwhich, when heated, is shapeable by molding or extrusion, includinginjection molding, blow molding and compression molding.
 32. A methodaccording to claim 31 in which the cellulose ether comprises at leastone ethylcellulose.
 33. (Cancelled).
 34. (Cancelled).
 35. A methodaccording to claim 1 in which said first cellulose derivative isselected from the group consisting of cellulose acetate, cellulosepropionate and cellulose nitrate.
 36. A method according to claim 1 inwhich said second cellulose derivative is selected from the groupconsisting of methylcellulose, carboxymethylcellulose and salts thereof,cellulose acetate phthalate, microcrystalline cellulose,ethylhydroxyethylcellulose, ethylmethylcellulose, hydrocyethylcellylose,hydroxyethylmethylcellulose, hydroxypropylcellulose,hydroxymethylcellulose and hydroxymethylpropylcellulose.
 37. A methodaccording to claim 36 in which said salt of carboxymethylcelllulose isselected from the group consisting of alkali metal and alkaline earthmetal salts.
 38. A method according to claim 1, in which saidplasticizer is selected from the group consisting of phosphate esters;phthalate esters; amides; mineral oils; fatty acids and esters thereofwith polyethylene glycol, glycerin or sugars; fatty alcohols and ethersthereof with polyethylene glycol, glycerin or sugars; vegetable oils andhydrogenated vegetable oils; nitrobenzene, carbon disulfide, β-naphtylsalicylate, phthalyl glycolate, and diocyl phthalate.
 39. A methodaccording to claim 38 in which said fatty alcohol is selected from thegroup consisting of cetostearyl alcohol, cetyl alcohol, stearyl alcohol,oleyl alcohol and myristyl alcohol.
 40. A method according to claim 1 inwhich said plasticizer is a non-ionic surfactant.
 41. A method accordingto claim 1, wherein the matrix composition does not contain polyethyleneglycol 2000 monostearate or polyethylene glycol 400 monostearate. 42.(Cancelled).
 43. (Cancelled).
 44. (Cancelled).
 45. (Cancelled). 46.(Cancelled).
 47. A method according to claim 1, wherein the polymer is apolyethylene oxide having a molecular weight of at least 100,000 daltonsand at the most 300,000 daltons.
 48. A method according to claim 1,wherein the pharmaceutically acceptable excipient is present and is amono-, di-, oligo or polycarboxylic acid selected from the groupconsistin of acetic acid, succinic acid, citric acid, tartaric acid,acrylic acid, benzoic acid, malic acid, maleic acid, and sorbic acid.49. A method according to claim 1, wherein the pharmaceuticallyacceptable excipient is present and is selected from mannitol, xylitol,sorbitol and inositol.
 50. A method according to claim 1, wherein thepharmaceutically acceptable excipient is an aluminium oxide.
 51. Amethod according to claim 1, wherein comprising PEO 200,000 as polymerand mannitol and/or aluminium oxide as pharmaceutically acceptableexcipient.
 52. A method according to claim 1, wherein thepharmaceutically acceptable excipient is an inorganic acid such asphosphoric acid including ortho phosphoric acid and meta phosphoricacid.
 53. A pharmaceutical composition for controlled release of atleast one therapeutically, prophylactically and/or diagnostically activesubstance into an aqueous medium by erosion of at least one surface ofthe composition, the composition comprising i) a matrix compositioncomprising a) a polymer or a mixture of polymers, b) an active substanceand, optionally, c) one or more pharmaceutically acceptable excipients,and ii) a coating having at least one opening exposing at the onesurface of said matrix, the coating comprising a) a first cellulosederivative which has thermoplastic properties and which is substantiallyinsoluble in the aqueous medium in which the composition is to be used,and at least one of b) a second cellulose derivative which is soluble ordispersible in water, c) a plasticizer, and d) a filler, and wherein thediffusion rate of the aqueous medium into the matrix compositioncorresponds to about 100%±30% such as, e.g. about 100%±25%, about100%±20%, about 100%±15% or about 100%±10% or about 100% of thedissolution rate of the matrix composition, and wherein any matrixsurface exposed to the aqueous medium erodes at a substantially constantrate, so as to obtain a zero order release of at least about 60% w/wsuch as, e.g. at least about 65% w/w at least about 70% w/w, at leastabout 75% w/w, at least about 80% w/w, at least about 85% w/w, at leastabout 90% w/w, at least about 95% w/w or at least about 97 or 98% w/w ofthe active substance from the pharmaceutical composition when subject toan in vitro dissolution test as described herein.
 54. A stablecontrolled release pharmaceutical composition for oral use comprising asolid dispersion of component i) and ii) i) at least onetherapeutically, prophylactically and/or diagnostically activesubstance, which at least partially is in an amorphous form, ii) apharmaceutically acceptable polymer that has plasticizing properties andwhich has a melting point or melting interval of a temperature of at themost 200° C., and, optionally, iii) a stabilizing agent, wherein the atleast one therapeutically, prophylactically and/or diagnostically activesubstance has a water solubility of at the most 3 mg/ml at 25° C. suchas, e.g. at the most about 2 mg/ml, at the most about 1 mg/ml, and theconcentration of the active substance in the composition corresponds toa concentration of at the most the saturated concentration in componentii) at a temperature corresponding to the melting point or the lowestend point of the melting interval of component ii) optionally togetherwith component iii).
 55. A composition according to claim 54, whereincomponent ii) is a polyethylene glycol and/or a polyethylene oxidehaving a molecular weight of at least about 20,000 in crystalline and/oramorphous form or a mixture such polymers.
 56. A composition accordingto claim 54, wherein component ii) is of a quality that ensures thatfree radicals formed, if any, do not significantly increase thedegradation of the active substance in the composition.
 57. Acomposition according to claim 53 or 54 comprising a stabilizing agent.58. A composition according to claim 54 comprising one or moreantioxidants that inhibits the formation of peroxides and/or inactivatesany peroxides present.
 59. A composition according to claims 53 or 54,wherein the composition is stable with respect to physical stability.60. A composition according to claims 53 or 54, wherein the compositionis stable with respect to in vitro dissolution of the active substancefrom the composition.
 61. A composition according to claim 60, whereinthe composition is stable with respect to in vitro dissolution behaviourin such a manner that t₅₀%, i.e. the time for 50% w/w of the activesubstance to dissolve in a dissolution medium, differs at the most ±20%w/w such as, e.g., at the most ±15% w/w, at the most ±10% w/w, at themost ±7.5% w/w, at the most ±5% w/w, at the most ±2.5% w/w, at the most±1.5% w/w or at the most 1% w/w when two compositions from the samebatch is compared with a time difference of 2 weeks under similarstorage and test conditions.
 62. A composition according to claims 53 or54, wherein the composition is stable with respect to chemical stabilityof the active substance.
 63. A composition according to claim 62,wherein the concentration of the active substance in the compositiondecreases at the most 20% w/w such as, e.g. at the most 15% w/w, at themost 10% w/w, at the most 7.5% w/w or at the most 5% w/w when stored atroom temperature for a time period of at least 3 months such as, e.g. 6months, 12 months, 18 months or 24 months and a relative humidity of atthe most 75% such as, e.g., at the most 70%, at the most 65%, at themost 60%, at the most 55%, at the most 50% or at the most 45%.
 64. Acomposition according to claims 53 or 54 containing carvedilol as activesubstance in a concentration of at the most about 23% w/w such as, e.g.,at the most about 22% w/w, at the most about 21% w/w or at the mostabout 20% w/w.
 65. A composition according to claim 64 containingcarvedilol as active substance and PEO 200,000 as component ii) andwherein the concentration of carvedilol in PEO 200,000 is at the mostabout 22% w/w, at the most about 21% w/w or at the most about 20% w/w.